Embryology Flashcards
Meromelia vs. Amelia
Meromelia: partial absence of limb due to inactivation of AER too early; phocomelia = no true long bones and flipper-like limbs
Amelia: complete absence of limb; inadequate limb mesenchyme with epithelium intact
Weeks 0-2
- Zygote
- Morula
- Blastocyst
- Embyroblast
- Inner cell mass
- Bilaminar disc: epiblast and hypoblast
- Trilaminar disc: cells invade called the primitive streak and form the ectoderm, mesoderm, and endoderm
Weeks 3-8 and Months 3-9
Weeks 3-8: All major organ systems develop
Months 3-9: Growth and Functional Maturation
Ectoderm
Epidermis of Skin
Neural Crest: sensory axons, spinal ganglion, melanocytes, and Schwann cells
Neural Tube: CNS and PNS
Mesoderm Differentiation
- Paraxial - medial; somitomeres (7 pairs) and somites (4 occipital pairs), which contribute to head development; cervicalcoccygeal have 33 pairs for postcranial development
- Intermediate - no contributions to limbs
- Lateral plate - lateral; splanchnic and somatic mesoderm; limb mesenchyme to make CT, appendicular skeleton, and vasculature
Somite Differentiation
Dermatome, Sclerotome, and Myotome
Embryonic Development: Weeks 4-8
week 4: limb bud formation; initiate vascular and nervous supply – including formation and completion of neural tube
week 6: paddle-shaped hand- and footplates; hyaline cartilage models form
week 7: limb rotation; muscle masses form
week 7-8: begin ossification process
Outgrowth of Limb Buds
upper limb buds (~day 24)
opposite lower 4 cervical & upper thoracic somites; C5-T2
lower limb buds (~day 28)
opposite lower 4 lumbar & upper 3 sacral somites; L2-S2
HOX Genes
location of limb buds – determined by homeobox (HOX) genes expression along the embryo
type/shape of limb bones – regulated by HOX genes along the proximodistal axis of the developing limb*
*HOX gene expression (determined by the combinatorial expression of (SHH, FGFs, and Wnt7a) occurs in phases in 3 places
Growth of Limb Regulation
Growth of limb - regulated by transcription factors and signaling molecules
Once positioning along the craniocaudal axis is determined (HOX genes), growth must be regulated along proximodistal, A-P, and D-V axes.
Limb outgrowth, which occurs first, is initiated by growth factors (FGF and TBX) secreted from lateral plate/somatic mesoderm.
Outgrowth of Limbs
- Ectodermal Cap
2. Mesenchymal core - (lateral plate mesoderm) secretes growth factors (FGF & TBX) which initiate outgrowth
Formation of AER
Apical Ectodermal Ridge (AER)
Once outgrowth is initiated, BMPs expressed in ventral ectoderm induce the formation of the AER via homeobox gene MSX2
Radical fringe in dorsal ectoderm restricts location of AER to distal tip of limb because AER causes cells to rapidly divide without differentiating called the progress zone. If the AER is not restricted, then cells would not differentiate properly proximodistally
SER separates cells that express radical fringe from those that are not; SER is close to AER
After the AER is established, it expresses FGF-4 and FGF-8 which maintain the Progress Zone (PZ)
Progress Zone
Maintained by the AER by secreting FGF
Cells that are rapidly dividing and not differentiating
Cells that leave the PZ differentiate:
Early mesoderm differentiation – proximal limb segment
Late mesoderm differentiation – distal limb segment
Most differentiated cells = zone of polarizing activity (ZPA)
SHH
FGF from AER induces SHH expression at ZPA via production of retinoic acid/ vitamin A
Wnt7a maintains SHH in ZPA to cause correct positioning of digits
SHH diffuses through the mesoderm creating a concentration gradient
Maintenance and propagation of SHH expression requires AER-FGF signaling as part of a positive epithelial–mesenchymal feedback loop between the ZPA and the AER
BMP-dependent downregulation of SHH is achieved by inhibiting FGF and Wnt signaling activities that usually maintain SHH expression
Polydactyly
occurs if two zones of polarizing activity (ZPA) or when ZPA is interrupted
Dorsoventral Axis Regulation
regulated by signaling molecules produced by ectoderm
Dorsal ectoderm – Wnt7a induces expression of Lmx1
Ventral ectoderm – BMPs induce expression of En1
(En1 represses Wnt7a expression restricting it to dorsal)
Establishing Axial Polarity
Proximodistal: controlled by AER secreting FGF
Pre/post axial (anteroposterior): controlled by ZPA producing retinoic acid that initiates SHH
Dorsoventral : regulated by Wnt7a (also maintains SHH) → LMX1 and BMPs → En1; signaling centers located in dorsal and ventral ectoderms
Development of Peripheral Vasculature
Initially: fine capillary network = marginal sinus (beneath AER) – venous outflow some channels preferentially enlarge, form large central artery pattern changes constantly by outgrowth, regression, coalescence. venous system (low pressure) more variable
Development of Joints
cell death and matrix changes in zones within cartilaginous rods
early joint development is independent of muscular activity
joint capsule, ligaments, & tendons from mesenchymal condensations
Development of Musculature
Paraxial mesoderm → somites → myotomes:
Epimere: intrinsic muscles of the back innervated by dorsal primary rami (deep muscles of back)
Hypomere: contribute to rest of muscles and superficial back too
Hypomere
Hypomere: contributes to muscles of extremities and then split up to dorsal and ventral aspects
Dorsal in the upper limb would be the pronators and supinators and the lower limb is adductors and abductors
Innervation of Limbs
All limbs are associated with ventral primary rami innervation
dorsal muscle mass innervated by dorsal (posterior) brs. of ventral rami of spinal nn.
ventral muscle mass innervated by ventral (anterior) brs. of ventral rami of spinal nn.
Arms: brachial plexus C5-T1
Legs: lumbosacral plexus L2-S2
Limb Rotation
Arms: rotate laterally to put extensors on the posterior aspect; coronal to parasagittal orientation
Legs: rotate medially to put extensors on the anterior aspect
Interdigital Space Formation
Digital rays appear, AER breaks up, leaving intact AER segments over digital ray tips (N=5 per hand/foot)
Reduces amount of FGF transmitted to interdigital spaces and cell death occurs
*Apical ectodermal ridge breaks down and FGFs are lost and begin to get programmed cell death to get the interdigital sapec
Syndactyly and Triphalangeal Thumb
No selected apoptosis with the AER of the hand/foot plate causes:
- Dysregulation of interdigital apoptosis = syndactyly
- Dysregulation of terminal apoptosis = triphalangeal thumb
Ectrodactyly
Lose apical ectodermal ridge = lose entire digit = ectrodactyly/cleft hand/cleft foot
Lobster claw deformity
HOX Gene Mutation
Problems with limb patterning causing:
- Synpolydactyly: multiple fused digits
- Short digits or fused carpal bones
*Both are HOX 13 mutations
Classification of Limb Defects
- Reduction defects – all or part of a limb is missing arrest of development, failure of differentiation (e.g., meromelia, amelia, phocomelia)
- Duplication defects – supernumerary limb elements (e.g., polydactyly)
- Dysplasia defects – malformation of the limb
overgrowth/undergrowth (e.g., macrodactyly, syndactyly, adactyly), focal defects (e.g., amniotic band syndrome),
general skeletal abnormalities (e.g., osteogenesis imperfecta)
Key Factors that cause Anomalies
Amount of mesenchyme available
Duration of the AER inductive influence
Presence of a teratogen
Mechanical factors
Teratogen vs. Morphogen
Teratogen – any agent or factor that induces or ↑ the incidence of a congenital anomaly in a developing embryo (i.e., factors that cause birth defects); weeks 3-8 are the most critical time that can be affected, especially weeks 4 and 5; months 3-9 defects are less severe/non-existent
Morphogen – signaling molecule that acts directly on cells to produce a specific response (i.e., a substance governing the pattern of tissue development - e.g., retinoic acid, FGF, Wnt, SHH)
Morphogens Become Teratogens
retinoic acid and receptors normally expressed in developing limb
altered synthesis and action:
if inhibited, limb formation halted
if excess, positional information disrupted
potential sources of excess:
excessive vitamin A intake (hypervitaminosis A)
products for treating acne containing isotretinoin (a retinoid or analogue of vitamin A)
Methyloxyethanol
Methyloxyethanol: extensively used in industry (paints, textile dyes, printing inks, brake fluid, semiconductor manufacture)
Regression of AER (due to reduced laminin content in the basal lamina of ectodermal cells) causing syndactyly (primarily upper limb)
Cadmium
Cadmium: extensively used in industry & agriculture; ubiquitous environmental pollutant
Damages DNA in embryonic cells causing limb deformities (syndactyly, polydactyly, hypertrophy)
Amniotic Band Syndrome
bands of amnion (inner lining of amniotic sac) or adhesions attach to fetus reduces local blood supply
causes abnormal development (including ring constrictions, and amputations)
Connective tissue strands from adhesions or breaks lose and then constrictions around the baby occurs = causes constrictions or amputations
Clubfoot (Talipes Equinovarus)
Plantarflexed, inverted, deformed talus, observed mainly in ♂
Likely etiology: abnormally low amniotic fluid (oligohydramnios) leading to mechanical pressure of uterine wall on fetus
Abnormal positioning of the legs in utero
Hereditary
