4: Developmental Biology of the Skin Flashcards
What are the central cells of the epidermis and what do they provide?
Keratinocytes are the central cells of the epidermis and they form the intermediate filament keratin, providing structural resiliency.
What is the role of fibroblasts in the skin?
Fibroblasts are the central cells of the dermis that secrete collagen, which provides the substance for the dermis.
What structures do appendages in the skin consist of?
Appendages are organized structures of keratinocytes and fibroblasts that make hair follicles, eccrine sweat glands, apocrine glands, and the nail unit.
Where do melanocytes predominantly reside and what do they synthesize?
Melanocytes predominantly reside in the epidermis and they synthesize melanin.
What is the function of Langerhans cells in the skin?
Langerhans cells are immune cells that reside predominantly in the epidermis and they internalize and present potentially harmful antigens to initiate an immune response.
What do sensory neurons monitor in the skin?
Sensory neurons monitor touch, pressure, temperature, and hair follicle movement.
What is the function of Merkel cells in the skin?
Merkel cells live in the epidermis and are responsible for sensing touch.
What are Wnt ligands and their role in skin development?
Wnt ligands are extracellular secreted proteins that stabilize β-catenin, which controls epithelial differentiation, stem cell function, and appendage function, leading to its nuclear translocation.
What is the significance of p63 in skin development?
p63 is a transcription factor with multiple isoforms that acts as a central regulator of epithelial identity; its absence leads to failure of epidermis stratification and appendage formation.
What do Shh ligands activate in skin development?
Shh ligands bind the smoothened receptor and activate the Gli family of transcription factors, which are crucial for hair follicle formation and function.
What is the role of EDAR in skin development?
EDAR is part of the tumor necrosis factor (TNF) receptor family and is involved in the development of appendages in the skin.
How do Notch ligands contribute to skin development?
Notch ligands Delta or Jagged bind the Notch receptor, initiating transcription and epidermal differentiation.
What is the function of BMP ligands in skin development?
BMP ligands regulate hair follicle cycling and growth.
What is the significance of HOX genes in skin development?
HOX genes are involved in large-scale body patterning, influencing the overall structure and organization of the skin.
A patient presents with a genetic mutation affecting the p63 transcription factor. What developmental abnormalities might you expect in their skin and appendages?
The absence of p63 leads to the failure of the epidermis to stratify or fully form, which results in the failure of appendage formation.
A researcher is studying a mouse model with defective Wnt signaling. What skin-related developmental processes might be impaired?
Defective Wnt signaling can impair epithelial differentiation, stem cell function, and appendage function, as Wnt ligands stabilize β-catenin, which is crucial for these processes.
A patient has a mutation in the EDAR gene. What specific skin appendages might be underdeveloped or absent?
Mutations in the EDAR gene can lead to underdevelopment or absence of appendages such as hair follicles and sweat glands.
A patient has a defect in the HOX genes. What large-scale developmental abnormalities might you expect?
Defects in HOX genes can lead to abnormalities in large-scale body patterning, including issues with dermal fibroblast development and body segmentation.
A patient has a genetic mutation affecting the Notch signaling pathway. What epidermal process might be impaired?
A mutation in the Notch signaling pathway can impair epidermal differentiation, as Notch signaling is crucial for this process.
A patient has a mutation in the BMP signaling pathway. What skin-related developmental processes might be affected?
A mutation in the BMP signaling pathway can affect hair follicle cycling and growth, as BMP ligands regulate these processes.
A patient has a genetic mutation in the Shh signaling pathway. What skin appendage might fail to develop properly?
A mutation in the Shh signaling pathway can impair hair follicle formation and function, as Shh ligands are crucial for this process.
A patient has a condition where their skin lacks Langerhans cells. What immune function might be impaired?
The absence of Langerhans cells can impair the skin’s ability to internalize and present harmful antigens, affecting immune response initiation.
What are the primary functions of keratinocytes in the skin?
Keratinocytes are the central cells of the epidermis that form the intermediate filament keratin and provide structural resiliency to the skin.
Describe the role of fibroblasts in skin development.
Fibroblasts are the central cells of the dermis that secrete collagen, providing the substance for the dermis and contributing to skin strength and elasticity.
What structures are formed by the organized structures of keratinocytes and fibroblasts?
The organized structures formed by keratinocytes and fibroblasts include hair follicles, eccrine sweat glands, apocrine glands, and the nail unit.
What is the primary function of melanocytes in the skin?
Melanocytes reside predominantly in the epidermis and are responsible for synthesizing melanin, which provides pigmentation to the skin.
How do Langerhans cells contribute to skin immunity?
Langerhans cells are immune cells that reside predominantly in the epidermis and internalize and present potentially harmful antigens to initiate an immune response.
What sensory functions do sensory neurons in the skin perform?
Sensory neurons in the skin monitor touch, pressure, temperature, and hair follicle movement.
What is the role of lymph vessels in the skin?
Lymph vessels in the skin return interstitial fluid to the circulatory system, helping to maintain fluid balance.
What is the significance of Merkel cells in the epidermis?
Merkel cells, which live in the epidermis, are responsible for sensing touch, contributing to the skin’s sensory functions.
Identify the main components of the immune cells found in the skin.
The immune cells in the skin include T cells, B cells, dendritic cells, macrophages, neutrophils, and mast cells.
What are Wnt ligands and their role in skin development?
Wnt ligands are extracellular secreted proteins that stabilize β-catenin, controlling epithelial differentiation, stem cell function, and appendage function.
Explain the function of Shh ligands in skin development.
Shh ligands are extracellular secreted proteins that bind the smoothened receptor, activating the Gli family of transcription factors, which are crucial for hair follicle formation and function.
What is the role of the Notch signaling pathway in skin differentiation?
The Notch signaling pathway is initiated when ligands Delta or Jagged bind the Notch receptor, leading to transcription and epidermal differentiation.
How do BMP ligands influence hair follicle development?
BMP ligands, or bone morphogenic proteins, regulate hair follicle cycling and growth, playing a critical role in hair development.
What is the significance of p63 in epidermal development?
p63 is a transcription factor with multiple isoforms that acts as a central regulator of epithelial identity; its absence can lead to failure in epidermal stratification and appendage formation.
Describe the function of EDAR in skin appendage development.
EDAR, or ectodysplasin A receptor, is part of the tumor necrosis factor (TNF) receptor family and is essential for the development of skin appendages.
What is the role of HOX genes in skin development?
HOX genes are involved in large-scale body patterning, influencing the spatial organization of skin structures during development.
What is the function of arterioles and venules in the skin?
Arterioles and venules connect to the cardiovascular system, playing a crucial role in blood circulation and nutrient delivery to the skin.
What is the significance of the epidermis in skin immunity?
The epidermis serves as a barrier to the outside world and is the locus of immune surveillance, helping to prevent and combat infections.
How do keratinocytes contribute to the skin barrier?
Keratinocytes form the outer layer of the epidermis, creating a protective barrier that prevents water loss and protects against environmental damage.
What is the role of immune cells in maintaining skin health?
Immune cells in the skin, such as T cells and dendritic cells, monitor for pathogens and initiate immune responses, maintaining skin health and integrity.
What is the impact of environmental factors on keratinocyte function?
Environmental factors such as UV radiation can affect keratinocyte function, leading to changes in differentiation and potential skin damage.
How do signaling pathways influence skin cell differentiation?
Signaling pathways like Wnt and Notch regulate the differentiation of skin cells, ensuring proper development and function of the epidermis and appendages.
What is the relationship between fibroblasts and skin aging?
Fibroblasts play a crucial role in maintaining skin structure; their decline with age can lead to reduced collagen production and signs of skin aging.
What is the role of the extracellular matrix in skin development?
The extracellular matrix provides structural support and biochemical signals that influence the behavior and differentiation of skin cells during development.
How do Shh ligands affect hair follicle development?
Shh ligands activate signaling pathways that are essential for the formation and function of hair follicles during skin development.
What is the importance of the dermis in skin structure?
The dermis provides the main structural substance of the skin, containing collagen and elastin that support the epidermis and house appendages.
How do immune cells in the skin respond to injury?
Immune cells in the skin respond to injury by migrating to the site, releasing cytokines, and initiating the healing process to restore skin integrity.
What is the function of the nail unit in skin development?
The nail unit is an organized structure that protects the distal phalanx and enhances the ability to grasp and manipulate objects, contributing to overall hand function.
What is the primary cell type found in the dermis and what is its main function?
The primary cell type found in the dermis is the fibroblast, which produces collagens and has a large repertoire of other functions.
What are the three germ layers formed during gastrulation and their contributions to skin development?
The three germ layers formed during gastrulation are: 1. Ectoderm - becomes the epidermis, melanocytes, and the nervous system. 2. Mesoderm - contributes to fibroblasts, blood vessels, muscles, and bone. 3. Endoderm - does not contribute to skin development, with some exceptions for fibroblast subpopulations originating from the ectoderm (neural crest).
How does the thickness of the epidermis vary in different areas of the body?
The epidermis is thicker in areas of the palms and soles due to increased pressure, while it is thinner in the eyelids.
What is the hypodermis and how does it relate to the skin layers?
The hypodermis, also known as subcutaneous tissue, transitions to the fascial layers and is characterized by an increase in adipocytes and a decrease in collagen.
What is the primary cell type found in the dermis and what is its main function?
The primary cell type found in the dermis is the fibroblast, which produces collagen and has a large repertoire of other functions.
How does the thickness of the epidermis vary in different areas of the body?
The epidermis is thicker in areas of the palms and soles due to increased pressure, and thinner in the eyelids.
What are the three germ layers formed during gastrulation and their contributions to skin development?
The three germ layers formed during gastrulation are: 1. Ectoderm - becomes the epidermis, melanocytes, and nervous system. 2. Mesoderm - contributes to fibroblasts, blood vessels, muscles, and bone. 3. Endoderm - does not contribute to skin development, with some exceptions for fibroblast subpopulations originating from the ectoderm (neural crest).
What is the role of keratinocytes in the epidermis?
Keratinocytes are the majority cell type in the epidermis, composed of structural protein keratin. They are stacked in layers of increasingly more mature states until they become effectively ghosts of cells.
What is the significance of the vernix caseosa during the third trimester of embryonic development?
The vernix caseosa is significant during the third trimester as it helps to lubricate the passage through the birth canal, facilitating delivery.
What are the main components of the hypodermis?
The hypodermis, also known as subcutaneous tissue, primarily consists of adipocytes and has a lower amount of collagen. It transitions to the fascial layers.
Describe the developmental stages of skin from the first to the third trimester.
The developmental stages of skin are as follows: 1. First Trimester (Weeks 0 to 12) - Organogenesis is mostly completed. 2. Second Trimester (Weeks 12 to 26) - Marked by continuous development, including the appearance of downy hair. 3. Third Trimester (Weeks 26 to 40) - Most development completes, including the formation of vernix caseosa.
What type of cells are found in the epidermis that pierce the basal lamina?
The epidermis contains nerve cells that pierce the basal lamina, which serves as a vital scaffolding structure separating the epidermis from the dermis.
What is the most abundant protein in the dermis and its significance?
Collagen is the most abundant protein in the dermis, providing structural support and strength to the skin.
What are the key developmental processes that occur in the first two weeks of embryonic development?
The first two weeks of embryonic development involve the most complicated steps, including morula, blastula, gastrula, and the processes of somatogenesis and organogenesis.
What role do neural crest cells play in the development of melanocytes and fibroblasts during fetal life?
Neural crest cells contribute to the formation of melanocytes and fibroblasts. They migrate during the third week of fetal life, with those in the head migrating even before neural tube.
What processes occur in the first two weeks of embryonic development?
The first two weeks involve the most complicated steps, including morula, blastula, gastrula, and the processes of somatogenesis and organogenesis.
What role do neural crest cells play in the development of melanocytes and fibroblasts during fetal life?
Neural crest cells contribute to the formation of melanocytes and fibroblasts. They migrate during the third week of fetal life, with those in the head migrating even before neural tube closure to form dermal fibroblasts in the face and anterior scalp.
What are the stages of epidermis differentiation after gastrulation?
The stages of epidermis differentiation are: 1. Periderm formation 2. Intermediate layer formation 3. Full maturation. Epidermal development begins soon after gastrulation, although it is mostly complete in the first trimester, it is not fully complete until after birth.
What are the consequences of defects in neural crest migration?
Defects in neural crest migration can lead to various conditions, including DiGeorge syndrome: associated with 22q11.2 deletion, resulting in defects in cardiac, craniofacial, and endocrine organs.
What is the significance of the gene p63 in epidermal differentiation?
The gene p63 is vital for epidermal differentiation and is expressed in the germinativum layer, which is a cuboidal, mitotically active, and undifferentiated layer. It is also noted to be corrupted in EEC syndrome.
What are the primary functions of fibroblasts in the dermis?
Fibroblasts, the primary cell type in the dermis, have several key functions: Secrete collagens and other extracellular matrix molecules. Support the structural integrity of the dermis. Contribute to the overall maintenance and repair of the skin.
What keratin-related developmental issue might cause extremely thin and fragile epidermis in a newborn?
The condition could be due to a lack of development of keratins, which is associated with blistering epidermolysis bullosa diseases.
What embryonic structure might be involved in abnormal dermis development in the face and anterior scalp?
The abnormal development could be due to issues with neural crest cells, which contribute to dermal fibroblasts in the face and anterior scalp.
What developmental layer might be missing in a patient with skin forming pathologic adhesions to adjacent epithelium?
The condition could be due to the absence of the periderm layer, which prevents pathologic adhesions to adjacent epithelium.
What protein or enzyme might be defective in a patient whose skin lacks an impermeable barrier?
The condition could be due to defects in filaggrin protein, keratins of the suprabasal layer (KRT1 and KRT10), or enzymes like transglutaminases that crosslink proteins to form an impermeable layer.
What embryonic migration process might be defective in a patient with skin lacking melanocytes in certain areas?
The condition could be due to defects in neural crest cell migration, which contributes to melanocyte development.
What epidermal developmental process might be impaired by a genetic mutation affecting the IRF6 gene?
A mutation in the IRF6 gene can impair periderm formation, which is crucial for epithelial maturation and preventing pathologic adhesions.
What developmental stage might be impaired in a patient with defects in the establishment of a skin barrier such as ichthyoses syndromes?
The condition could be due to defects in the formation of the intermediate layer, which develops around 60 days EGA between the periderm and germinativum layer.
What lipid-metabolizing enzyme might be defective in a patient with skin lacking proper cornification?
The condition could be due to defects in lipid-metabolizing enzymes like ALOX, whose products are important for cornification.
What are the implications of a lack of periderm in epidermal development?
A lack of periderm can lead to human cocoon syndrome, which is characterized by pathologic adhesions to adjacent epithelium and can affect the overall maturation and function of the epidermis.
What are ichthyosis syndromes and how are they related to epidermal differentiation?
Ichthyosis syndromes, also known as defects in cornification, are conditions that arise from defects in the establishment of the skin barrier. The most common form, ichthyosis vulgaris, is linked to defects in the filaggrin protein present in keratohyalin granules in the upper epidermis.
What is the primary cell type in the dermis and what is its function?
The primary cell type in the dermis is the fibroblast, which supports the dermis by secreting collagens and other extracellular matrix molecules essential for structural integrity.
How do keratins contribute to the structure of the epidermis?
Keratins, specifically type I and type II keratins, are crucial for the structure of the epidermis. A lack of development of keratins can lead to conditions such as blistering epidermolysis bullosa, which affects the integrity of the skin.
What is the role of the mesoderm in the development of the dermis?
The mesoderm gives rise to the dermis, which is referred to as mesenchyme. This layer is essential for providing structural support and housing fibroblasts that secrete collagen and other matrix molecules.
What are the roles of upper and lower dermal fibroblast progenitors in skin development?
Upper dermal fibroblast progenitors (PDGFRa+, Blimp1+, Dlk−, Irig1+) become dermal papillae, which control hair keratinocytes and the arrector pili muscle, contributing to the upper dermis as papillary fibroblasts. Lower dermal fibroblast progenitors (PDGFRa+, Blimp1−, Dlk1+) differentiate into adipocytes and reticular fibroblasts, with a lesser density of collagen I compared to collagen III.
How do adipocytes contribute to skin physiology?
Adipocytes play a crucial role in energy balance, immune surveillance, and coordinating hair cycling. They store energy as lipids (white adipose) and burn energy through uncoupling oxidative phosphorylation to generate heat (brown adipose).
What is the significance of melanocyte differentiation during embryonic development?
Melanocytes can be detected by the eighth week of development, originating from SOX10-positive progenitors. The differentiation process is regulated by MITF, a critical transcription factor.
What are the stages of hair follicle development?
The stages of hair follicle development include: 1. Formation of hair placode (around 75 days EGA) 2. Hair germ phase (80 days EGA) 3. Peg stage (100 days EGA) 4. Lanugo hair production (130 days EGA). These stages are influenced by signals such as Wnt, BMP, and FGF.
What are the clinical implications of defects in melanocyte development?
Defects in melanocyte development can lead to conditions such as piebaldism, which is characterized by disrupted melanocyte migration due to defects in signaling pathways like c-kit.
What transcription factor might be deficient in a fetus showing delayed development of melanocytes?
Delayed melanocyte development could be due to a deficiency in MITF (microphthalmia-associated transcription factor), which is critical for melanocyte differentiation.
Which signaling pathway or gene might be implicated in a patient lacking sweat glands and hair follicles?
The ectodysplasin ligand (EDA) and receptor (EDAR) pathway might be implicated, as it is essential for the development of hair follicles and sweat glands.
What signaling pathway might be defective in a patient with areas of albinism due to disrupted melanocyte migration?
Disrupted melanocyte migration could be due to defects in the c-kit growth factor signaling pathway.
What adipose-related abnormalities might you expect from a mutation in the PPARγ transcription factor?
A mutation in PPARγ can lead to defects in both white and brown adipose tissue development, affecting energy storage and heat generation.
What gene might be mutated in a patient with a rare syndrome characterized by fat herniations and ulcers along Blaschko lines?
The condition could be due to mutations in the PORC gene, which is involved in Wnt molecule secretion, leading to focal dermal hypoplasia or Goltz syndrome.
What sensory function might be impaired in a patient lacking Merkel cells?
The absence of Merkel cells can impair the sense of touch, as these cells act to tune mammalian touch receptors.
What melanocyte-related process might be overactive in a patient with excessive pigmentation in certain areas?
Excessive pigmentation could be due to overactive melanocyte differentiation or increased expression of MITF and TYR (Tyrosinase).
What skin-related developmental processes might be affected by a genetic mutation in the FGF signaling pathway?
A mutation in the FGF signaling pathway can affect hair follicle development and patterning, as FGF is involved in these processes.
What hair-related abnormalities might you expect in a patient lacking dermal papillae?
The absence of dermal papillae can impair hair keratinocyte control, leading to defects in hair follicle development and cycling.
What developmental progenitor might be defective in a patient whose skin lacks adipocytes?
The condition could be due to defects in lower dermal fibroblast progenitors, which give rise to adipocytes.
What developmental phase might be defective in a patient whose skin lacks sebaceous glands?
The condition could be due to defects in the bulbous peg phase, during which sebaceous glands develop from SOX9+ LRIG1+ hair follicle keratinocyte stem cells.
What dermal progenitor might be defective in a patient whose skin lacks arrector pili muscles?
The condition could be due to defects in upper dermal fibroblast progenitors, which give rise to arrector pili muscles.
What adipose-related cell type might be defective in a patient lacking proper immune surveillance?
The condition could be due to defects in adipocytes, which play a role in immune surveillance.
What melanocyte-related process might be defective in a patient whose skin lacks proper pigmentation in the hair?
The condition could be due to defects in melanocyte differentiation or the expression of TYR (Tyrosinase), which is crucial for hair pigmentation.
What epidermal cell type might be defective in a patient whose skin lacks proper touch sensitivity?
The condition could be due to defects in Merkel cells, which are responsible for tuning mammalian touch receptors.
What is the role of MITF in melanocyte differentiation?
MITF (microphthalmia-associated transcription factor) is a critical transcription factor for melanocyte differentiation, regulating the expression of genes necessary for the development and function of melanocytes, including DCT and KIT proteins.
How does the loss of MITF and KIT expression affect melanocyte development?
Loss of expression of MITF and KIT leads to the reversion of melanocytes to a melanoblast state, which can affect the population of adult melanocyte stem cells residing in the hair follicle bulge stem cell compartment.
At what stage can melanocytes be detected during development, and what is their precursor?
Melanocytes can be detected by the eighth week of development, originating from SOX10-positive progenitors.
How does the loss of MITF and KIT expression affect melanocyte development?
Loss of expression of MITF and KIT leads to the reversion of melanocytes to a melanoblast state, which can affect the population of adult melanocyte stem cells residing in the hair follicle bulge stem cell compartment.
At what stage can melanocytes be detected during development, and what is their precursor?
Melanocytes can be detected by the eighth week of development, originating from SOX10-positive progenitors, which are also precursors for glial cells.
What are the key signals involved in hair follicle development?
Key signals involved in hair follicle development include Wnt, BMP, and FGF (fibroblast growth factor), which play crucial roles in the patterning and morphogenesis of hair follicles during embryonic development.
Describe the stages of hair follicle development from the hair placode to the peg stage.
The stages of hair follicle development include: 1. Hair placode formation (around 75 days EGA) - keratinocytes become thinner and tightly packed. 2. Hair germ phase (80 days EGA) - downward movement of epithelium forming a clear nubbin. 3. Peg stage (100 days EGA) - continued downward epithelial invasion, wrapping around inductive fibroblast population (dermal papillae).
What is the significance of the bulge stem cell compartment in hair follicle cycling?
The bulge stem cell compartment is crucial for maintaining normal hair cycling, as it contains stem cells that regenerate hair follicles through repeated cycles of apoptosis and regeneration, ensuring continuous hair production.
What are the characteristics of sebaceous glands during development?
Sebaceous glands develop during the bulbous peg phase from SOX9+ LRIG1+ hair follicle keratinocyte stem cells and are more active during embryogenesis and puberty, typically associated with hair follicles.
How does the presence of dermal melanocytes change from development to adulthood?
Dermal melanocytes are present in greater numbers during development and persist after birth in specific areas such as the dorsa of the hands and feet, sacrum/buttocks, and scalp, which are common sites for conditions like blue nevi.
What is the clinical significance of piebaldism in relation to melanocyte migration?
Piebaldism is characterized by disrupted melanocyte migration due to defects in signaling pathways, such as c-kit growth factor signaling, leading to areas of albinism and highlighting the importance of proper melanocyte distribution in skin pigmentation.
What is the role of Merkel cells in the development of cutaneous nerves?
Merkel cells develop from basal-layer keratinocytes and act as touch receptors, playing a significant role in the sensory innervation of the skin, with high density found at volar sites and appendages as early as 12 weeks EGA.
What are the developmental origins of sensory neurons in the skin?
Sensory neurons in the skin develop from the trigeminal ganglia (for the head) or dorsal root ganglia (elsewhere), indicating their neural crest origin and involvement in sensory function.
How do clinical syndromes like Berardinelli-Seip affect adipose tissue development?
Berardinelli-Seip syndrome is characterized by defects in the lipid synthesizing AGPAT2 gene, leading to significant issues in adipose tissue development and function, highlighting the genetic basis of lipodystrophy syndromes.
What is the significance of β-catenin in hair follicle development?
β-catenin is crucial in the initiation of hair follicle development, particularly in keratinocytes and fibroblasts, and is essential for the morphogenesis of appendages during embryonic development.
What are the downstream genes involved in hair follicle morphogenesis?
Downstream genes involved in hair follicle morphogenesis include ectodysplasin ligand (EDA) and its receptor (EDAR), which are essential for the development of hair follicles and sweat glands, with mutations leading to syndromes of reduced appendage formation.
What is the role of SOX9 in sebaceous gland development?
SOX9 is a key transcription factor involved in the development of sebaceous glands, which arise from hair follicle keratinocyte stem cells during the bulbous peg phase of embryogenesis.
How does the presence of interfollicular melanocytes change during UV light therapy for vitiligo?
During UV light therapy for vitiligo, there is a dramatic increase in the supply of interfollicular melanocytes, which are crucial for restoring pigmentation in affected areas of the skin.
What are the characteristics of brown adipose tissue and its development?
Brown adipose tissue is characterized by its ability to burn energy through uncoupling oxidative phosphorylation, and its development is regulated by factors such as Prdm16, which is essential for brown adipose differentiation.
What is the relationship between hair follicle development and the presence of dermal papillae?
Dermal papillae are essential for hair follicle development as they provide inductive signals to the overlying epithelium, facilitating the growth and cycling of hair follicles through interactions with stem cells.
How does the density of collagen differ between upper and lower dermal fibroblasts?
Upper dermal fibroblasts have a greater density of collagen III, while lower dermal fibroblasts exhibit a greater density of collagen I, reflecting their distinct roles in skin structure and function.
What is the significance of the hair germ phase in hair follicle development?
The hair germ phase (80 days EGA) is significant as it marks the formation of the hair bud, where epithelial cells begin to proliferate and move downward, setting the stage for subsequent hair follicle development.
What are the implications of defects in the signaling pathways involved in hair follicle development?
Defects in signaling pathways such as Wnt, BMP, and FGF can lead to abnormal hair follicle development, resulting in conditions characterized by reduced hair density or absence of hair follicles, impacting skin health and appearance.
What are the roles of EDAR and HOX in skin development?
EDAR is involved in the development of sweat glands and nails, while HOX is specifically related to nail development.
What is the significance of volar dermatoglyphics in embryonic development?
Volar dermatoglyphics begin around week 7 EGA with the appearance of volar pads, which are accumulations of grouped fibroblasts. As these pads involute, epidermal ridges form due to local hyperproliferation of the basal layer of the epidermis.
How do angioblasts contribute to skin vasculature?
Angioblasts are stem cells derived from mesoderm that respond to signals such as Indian hedgehog (Ihh), FGF2, BMPs, and VEGF. They differentiate into endothelial cells, which are crucial for forming blood vessels in the skin.
What is the hallmark disease associated with GNAQ gene defects?
The hallmark disease is Sturge-Weber syndrome, characterized by prominent port-wine stains on the face and intracranial vascular anomalies, which can lead to seizures and mental retardation.
What is the role of Langerhans cells in the skin?
Langerhans cells are generated from the yolk sac and contribute to skin immunity. They appear around 10 weeks of gestation and are important for maintaining tissue memory T cells in the skin, which are crucial for immune responses.
What is mosaicism in embryonic development?
Mosaicism refers to a condition where an embryo acquires a novel mutation during development, leading to patterns such as Blaschko’s lines, which can manifest as linear expansions or curving patterns of the growing mutant clone affected by the mutation.
A patient presents with chronic eczema and recurrent skin infections. Genetic testing reveals a STAT3 mutation. What syndrome might this indicate?
This indicates hyperimmunoglobulin E syndrome (Job syndrome), characterized by impaired T-helper cell 17 (TH17) development and excessive T-helper cell 2 (TH2) profile.
A patient has a port-wine stain on their face and intracranial vascular anomalies. What genetic mutation might be responsible?
The condition is likely caused by a mutation in the GNAQ gene, associated with Sturge-Weber syndrome.
A patient has a condition where their skin shows linear or curving patterns of pigmentation. What developmental phenomenon might explain this?
The condition could be due to mosaicism, where an embryo acquires a novel mutation during development, leading to patterns like Blaschko’s lines.
A patient has a genetic mutation affecting the VEGF signaling pathway. What vascular abnormalities might you expect in their skin?
A mutation in the VEGF signaling pathway can lead to abnormalities in vasculature density and lymphatic development, as VEGF is crucial for these processes.
A patient has a genetic mutation affecting the formation of volar dermatoglyphics. What embryonic structure might be abnormal?
The condition could be due to abnormalities in volar pads, which are accumulations of grouped fibroblasts that form around week 7 EGA.
A patient has a genetic mutation in the PROX1 gene. What lymphatic-related abnormalities might you expect?
A mutation in the PROX1 gene can impair lymphatic development, as PROX1 is crucial for the maturation of venous endothelial cells into lymph vessels.
A patient has a condition where their skin lacks proper vascular density in the scalp. What signaling molecules might be deficient?
The condition could be due to deficiencies in signaling molecules like VEGF, Netrins, Slit, and Semaphorins, which regulate vascular density.
What is the significance of volar pads in embryonic development?
Volar pads, which appear around week 7 of embryonic gestational age (EGA), are accumulations of grouped fibroblasts that lead to the formation of epidermal ridges as they involute, indicating local hyperproliferation of the basal layer of the epidermis.
How do angioblasts contribute to skin vasculature?
Angioblasts are stem cells derived from mesoderm that respond to signals such as Indian hedgehog (Ihh), FGF2, and VEGF to differentiate into endothelial cells, which are crucial for forming blood vessels in the skin.
What is the clinical significance of Sturge-Weber syndrome in relation to vascular development?
Sturge-Weber syndrome is characterized by defects in the GNAQ gene, leading to prominent port-wine stains and intracranial vascular anomalies, which can result in seizures and mental retardation due to abnormal vascular development.
What is the role of Langerhans cells in the skin?
Langerhans cells, which begin to develop around 10 weeks of gestation, are crucial for maintaining immunity in the skin and are generated from the yolk sac during early development.
What are the implications of hyper-IgE syndrome on T-helper cell development?
Hyper-IgE syndrome, also known as Job syndrome, results from STAT3 mutations that impair the development of T-helper cell 17 (TH17), leading to an excessive T-helper cell 2 (TH2) profile, which is associated with chronic eczema and recurrent Staphylococcus aureus infections.
What is mosaicism in embryonic development?
Mosaicism refers to a condition where an embryo acquires a novel mutation during development, leading to distinct patterns of growth, such as Blaschko’s lines, which can manifest as linear expansions or curving patterns of the mutant clone.
How does lymphatic development occur in the skin?
Lymphatic development in the skin arises from the maturation of established venous endothelial cells that express PROX1, leading to the formation of lymph vessels in regions where VEGF-C is expressed in the lateral mesoderm.
What factors influence the density of vasculature in different skin sites?
The density of vasculature in skin varies by site, influenced by local cues such as Netrins, VEGF, Slit, and Semaphorins, which guide the development of blood vessels in areas like the scalp compared to the back dermis.
What is the significance of resident tissue memory T cells in the skin?
Resident tissue memory T cells in the skin play a vital role in maintaining immunity and are present in adults, but not in embryos, highlighting their importance in postnatal immune responses.
How many weeks AOG?
- Gastrulation begins
- Ectoderm is formed
- Single layer germinativum
How many weeks AOG?
- Periderm forms
How many weeks AOG? :
- Intermediate layer forms
- Melanocytes present
- Distinct boundary between epidermis and dermis
- Dental placodes forming
How many weeks AOG?
- Nail placodes form
How many weeks AOG?
10
How many weeks AOG?
12
How many weeks AOG?
13
How many weeks AOG?
24
Germinativum is composed of mitotically active cuboidal cells and is where skin forming starts. It derives from what embryonic layer?
Ectoderm.
Germinativum expresses what marker, which is corrupted in Ectrodactyly–ectodermal dysplasia–cleft syndrome?
P63.
This skin layer is the locus of immune surveillance and activation.
Epidermis
This skin layer provides the main structural substance of skin. It forms a main interface to vasculature and nervous system in the skin.
Dermis
This skin layer is characterized by subcutaneous adipose tissue with a role in energy balance, as well as recently defined roles in epidermis crosstalk and immune surveillance.
Hypodermis
This transcription factor is the central regulator of epithelial identity and without it there will be failure of appendage formation.
P63
These extracellular secreted proteins bind the smoothened receptor, activate Gli family of transcription factors and play a role in hair follicle formation and function.
Shh ligands
A part of the TNF receptor family critical for appendage development.
EDAR (ectodysplasin A receptor)
These extracellular secreted proteins have important posttranslational modifications such as palmitoylation and activate the frizzled receptors to eventually stabilize b-catenin,
causing its nuclear translocation from cytoplasmic-associated or cytoskeletal-associated structures.
Wnt ligands
This controls epithelial differentiation, stem cell function, appendage function.
β-Catenin
These ligands bind the receptor
Notch which initiates transcription and epidermal differentiation.
Delta / Jagged
These are a family of ligands that,
among other functions, regulate hair follicle cycling and growth.
BMP (bone morphogenic protein) ligands
This transcription factor family is
important in large-scale body patterning.
HOX (homeobox)
The _____ trimester is marked by continuous development, for example, the appearance of downy
hair in the infant.
2nd (weeks 12 - 26)
The _____ trimester is when most development completes, including the formation of the vernix caseosa from the skin whose function is thought to lubricate for the passage through the birth canal.
3rd (weeks 26 - 40)
As the ICM (inner cell mass) differentiates into 3 germ layers it becomes the _____, which is the
first stage where skin development separates from the development of other organs.
gastrula
The ectoderm forms what skin components?
Epidermis
Melanocytes
Nervous system
The mesoderm forms what skin components?
Fibroblasts
Blood vessels
Muscles
Bone
The endoderm forms what skin components?
It does not contribute to skin development.
Neural crest development is important in the skin as it contributes to structures such as _____ and
_____.
Melanocytes
Fibroblasts
In the head, the neural crest migrate
even before neural tube closure, and contribute to dermal fibroblasts in the _____ and _____.
Face
Anterior scalp
Most abundant protein in the epidermis?
Keratin
Most abundant protein in the dermis?
Collagen
Neural crest cells secrete the _____ ligand.
Wnt1
Persistent neural crest cells that do not complete migrations and differentiate into melanocytes are hypothesized to contribute to _____.
Common blue nevi
In the _____ week AOG, the mesoderm condenses into regular-spaced cuboidal segments termed somites (lateral to the neural tube).
3rd
Somites contribute to the axial skeleton and muscles and what skin component?
Dermal fibroblasts (e.g. back—from the dorsolateral portions of the somite, i.e. dermatomyotome)
Defects in neural crest migration affect what skin cells?
Melanocytes
Non–melanocyte-related diseases of neural crest migration result to what syndrome?
DiGeorge syndrome where 22q11.2 deletion results in defects in cardiac, craniofacial, and endocrine organs.
The final layers of epithelium consist of unique pairs of both a type I keratin and a type II keratin. Lack of development of keratins leads to what diseases?
Blistering epidermolysis bullosa diseases
Fibroblasts
- from the ventral body derive from _____
- from the head derive from _____
- from the back derive from _____
Lateral Plate Mesoderm
Neural crest precursors
Somites
What are 2 hallmark clinical syndromes of defects in mesenchymal development?
- Focal dermal hypoplasia or Goltz
syndrome (mutations in the PORC gene for Wnt molecule secretion) - fat herniations appearing as soft yellow to red nodules appearing in Blaschko lines and ulcers at sites of absent skin - Lipodystrophy syndromes such as Berardinelli-Seip (defects in the lipid
synthesizing AGPAT2 gene)
It is a critical transcription factor for melanocyte differentiation.
MITF (microphthalmia-associated transcription factor)
Loss of expression of MITF and KIT causes melanocytes to revert to a melanoblast. What are melanoblasts?
They are the adult melanocyte stem cells that live in the hair follicle bulge stem cell compartment. They may differentiate into mature melanocytes
(expressing TYR [Tyrosinase]) that populate the hair follicle to give pigment to the hair. They are home to sweat glands, which is the pathology behind acral melanoma. They supply interfollicular melanocytes as well, most dramatically during UV light therapy for patients with vitiligo.
Dermal melanocytes persist after birth in what areas?
Dorsa of the hands and feet
Sacrum/buttocks
Scalp
Blue nevi
This results from disrupted melanocyte migration secondary
to defects in, e.g., c-kit growth factor signaling, leading to areas of albinism.
Piebaldism
Merkel cells act to tune the _____ receptor.
They derive from _____.
They are found as early as _____ weeks EGA.
They around found with high density at _____, _____, and _____.
Mammalian touch receptor
Basal layer keratinocytes
12
Volar sites, appendages, nerves
_____ in keratinocytes and fibroblasts initiate hair follicle development; it is most important for appendage development.
β-catenin
Stages of hair follicle development?
Site of hair follicle stem cell compartment?
Bulge
What are downstream genes and receptors for hair follicle morphogenesis whose mutations cause syndromes where individuals
are born with fewer hair follicles and sweat gland?
Ectodysplasin ligand (EDA) and receptor (EDAR)
Sebaceous glands develop during the _____ phase.
bulbous peg
Keratin marker of SURFACE ECTODERM seen at week 4-5 EGA?
K8/K18
Keratin marker of PERIDERM seen at week 5-6 EGA?
K8/K18
Keratin marker of INTERMEDIATE LAYER seen at week 8-10 EGA?
K1/K10
Keratin marker of BASAL LAYER seen at week 12 EGA?
K5/K14
Sebaceous glands derive from _____ at _____ weeks EGA and are more active during _____ and _____.
SOX9+ LRIG1+ hair follicle keratinocyte stem cells
13-14
Embryogenesis, puberty
Sebaceous glands classically are associated with hair follicles but variations such as orphan sebaceous glands exist, namely:
_____ of the eye;
_____ of the mouth;
_____of the prepuce;
and the _____ of the female areola.
Meibomian gland
Fordyce spots
Tyson glands
Montgomery glands
In adnexal development the following ligands are important:
_____ for sweat gland and nail development
_____ for nail development
EDAR
HOX
These glands are found in the hormonally responsive areas of the axillae and genitals.
Apocrine
Volar dermatoglyphics begins around week _____ EGA when protuberances in
palms and soles, called volar pads (accumulations of grouped fibroblasts) appear.
7
_____ are stem cells of the vasculature and derive from mesoderm. Their signals include _____, _____, _____, and _____.
Angioblasts
Indian hedgehog (Ihh)
FGF2
BMPs
Vascular endothelial growth factor (VEGF)
_____ are differentiated angioblasts. They express signals _____ and _____.
Endothelial cells
TGF-B
PDGF
This is required for the recruitment of
associated cells such as pericytes.
Angiopoietin-1
Differential density of vasculature according to skin site—such as the higher density of vessels in the scalp
versus the back dermis—from local cues such as from _____, _____, _____, and _____.
Netrins
VEGF
Slit
Semaphorins
Hallmark disease of vasculature development? What is the gene involved and how does this present?
Sturge-Weber syndrome where defects in the gene GNAQ cause prominent port-wine stains on the face, as well as intracranial vascular anomalies leading to seizures and mental retardation.
This is the first to contribute to hematopoietic stem cells in the skin and generates Langerhans cells at 10 weeks EGA.
Yolk sac
This contributes to the second wave of development of HSCs.
Dorsal aorta
This provides the later contributions to the development of HSCs.
Liver
Hallmark syndrome of defects of HSC development? What is the gene involved and how does it present?
Hyperimmunoglobulin E (Hyper-IgE) syndrome or Job syndrome - signal
transducer and activator of transcription 3 (STAT3) mutations. There is impaired T-helper cell 17 (TH17) development and, instead, to excessive T-helper cell 2
(TH2) profile of eosinophilia and hyperIgE; characterized by chronic eczema and recurrent skin Staphylococcus aureus infections.
A condition where an embryo acquires a novel mutation in the process of development.
Mosaicism
Most classic presentation of mosaicism?
Blaschko’s lines, that consists of either
linear expansions, or curving patterns of the growing mutant clone that are affected by the new mutation.
