Exam 2: Embryology Flashcards
Functional Differentiation
Series of regulatory steps that determine the “when, where, and how” a gene that produces a functional protein is expressed.
Embryonic Developmental
Processes
- Cell proliferation
- Cell specialization
- Cell-to-cell interactions
- Cell movement
Differentiation
The transition of cells from pluripotency to its specific functional state.
Induction
One population of cells produces signal molecules to guide the development of a neighboring population of cells into a specific tissue or organ.
Inductor ⇒ cell or tissue producing the signal molecule
Competent tissue ⇒ responding group of cells or tissues
Fate
When a specific region of the embryo regularly gives rise to the same tissue or structure.
Cells commit to a particular fate based on their location within the embryo and stage of development ⇒ developmental field.
Chemical communication between cells ensures that all fates are properly allocated and pattern of allocation is coherent.
Divergent Developmental Pathways
Simple binary options ⇒ cells become comitted to one of two fates
Multiple fate options ⇒ intricate branching patterns
Simple Binary Developmental Pathway
Concentration of regulatory molecules determines on/off switch.
Above a threshold level, the “on” path is taken ⇒ alternative pathway
“Off” path implies that developmental pathways will proceed along the path that had been determined by previous decisions ⇒ default pathway
Forming Complex
Patterns
Developmental responses more finely graded by the concentration fo a signal molecule.
Usually involves generation of the molecule from a localized source and allowing simple diffusion to create a gradient.
Morphogenesis
The process where a 3D structure is formed through changes in cell shape, cell adhesion, and/or cell death.
Morphogens
Diffusible molecules through which one group of cells influences neighboring group of cells to follow a developmental route.
Intracellular Gradients
- Promotes cellular polarity and asymmetrical cell division
- Can be composed of mRNA, proteins, or other intracellular components
- Allows events to occur differently within regions of the cell
Extracellular Gradients
- External morphogen gradients can influence cell development
- Able to regulate whole fields of cells to develop into specific tissues and organs
- Regions with multiple gradients originating from different sources
- Allows cells within the field to judge their position
- Very small differences in morphogen concentration can lead to distinct fates
Positional Information
Utilization
Cells must be there to respond to the positional information provided by extracellular gradients.
Requires that competent cells respond by making one or more specific transcription factors.
Nature and concentration of the transcription factors regulate cellular protein production in a coordinated fashion.
Developmental Gene
Classes
-
Gene regulatory proteins
- promote or inhibit gene expression
- control protein modification
- determines the functional protein profile in the cell
-
Communication proteins
- used for cell signaling and cellular adhesion
- soluble mediators
- membrane-bound ligands
- receptors
Together allow organism’s cells to behave independently while promoting development in an organized, integrated manner.
HOX Genes
Encodes transcription factors that act as “master switches”
-
Regulate the expression of a large set of downstream genes
- Critical for the morphogenesis of different body parts
-
Important in establishment of the cranio-caudal axis
- somites, limbs, vertebrae, and craniofacial structures
- 39 HOX genes expressed sequentially throughout embryo
- Starts during embryogenesis and continues throughout
- Regulated by DNA-binding proteins that alter chromatin
Synpolydactyly
Caused by mutation in HOXD13
HOX genes with significant role in limb development.
Results in interphalangeal webbing and extra digits.
Vitamin A
Retinoic acid required for the normal expression of HOX genes.
-
Too little ⇒ pattern of malformations
- eyes
- GU tract
- cardiovascular system
- diaphragm
- lungs
-
Too much ⇒ severe birth defects
- CNS
- Cardiac
- craniofacial defects
Retinoic Acid Embryopathy
Infants in mothers treated for acne with Accutane or Soriatane.
Elevated levels of retonoic acid resulted in severe birth defects.
Dosing and timing of exposure determined the change in gene expression and range of structural congenital malformations.
PAX Genes
- Transcription factors important in development.
- Act singly rather than in temporal or spatial combination.
- Mutations in different PAX genes can lead to many different manifestations based on expression pattern.
Type I Waardenburg
Syndrome
- Caused by loss-of-function mutation in PAX3 gene
- Autosomal dominant
-
Reduction or deficiency in neural crest derivatives
- Melanocytes
- white forelock
- pale asymmetrical colored eyes
- Sensorineural deafness
- CT of face and head
- wideset eyes
- Somite-derived tissue of upper limbs
- upper extremity defects
- Melanocytes
Type II Waardenburg Syndrome
Caused by a mutation in the MITF transcription factor.
MITF is normally induced by PAX3.
Expression limited to pigment cells.
Results in white forelock and deafness.
Other Important Developmental
Transcription Factors
-
SOX gene (SRY-type HMG box)
- involved in sex determination
-
TBX gene
- have both activator and repressor domains
- involved in mesoderm and notochord differentiation
-
Zinc finger genes
- bind DNA through finger-like loops
Sonic Hedgehog
(SHH)
Morphogen that considered the “master signal” in development.
- SHH gradient prompts cells to differentiate into structures depending on the concentration
-
Expressed in many embryonic tissues and developmental processes
- Limb buds
- Notochord
- Neural tube
- Cardiovascular development
- Left-right axis formation
- Gut, pharynx, and lungs
- Synthesized as an inactive precursor that requires addition of a cholesterol
- Binds to the Patched (Ptc) receptor
- Binding blocks Patched inhibition of the Smoothened protein
- Allows activation of the SHH pathway
Neural Tube
Differentiation
-
SHH and BMP act as opposing morphogens
- Notochord and floor plate cells (ventral) make SHH
- Roof plate cells (dorsal) make bone morphogentic proteins
- Resulting gradient induces differential expression of gene regulatory proteins at different dorsoventral levels
- Promotes formation of the dorsoventral axis
-
Promotes cell and tissue organization in the brain and spinal cord
- Cells next to floor plate ⇒ high SHH ⇒ become motor neurons
- Cells near roof plate ⇒ high BMP ⇒ become sensory neurons
Limb Bud
Differentiaton
- Limb buds appear at 28 days post-fertilization
-
Apical ectodermal ridge (AER) cells at limb tip secrete FGF
- maintains further growth
- establish proximal/distal axis of limb ⇒ long axis
- divides limb into preaxial and postaxial segments
- Retinoic acid ⇒ ⊕ HOX genes ⇒ ∆ FGF expression
- Mesenchymal cells in the zone of polarizing activity secrete SHH
- creates a gradient that determines prexial to postaxial organization of the limb
- Cells in mesodermal core exposed to complex morphogen gradients ⇒ ∆ HOX expression ⇒ ∆ downstream gene products ⇒ ∆ local cell activity
- Mesodermal mesenchyme in progress zone kept in an undifferentiated state by FGF from the AER.
- New mesoderm made ⇒ progress zone and AER move distally ⇒ FGF influence on proximal part ↓ ⇒ limb differentiates from proximal to caudal
- Late in week 6, distal portion forms hand and foot plates
- AER splits into 5 parts to guide formation of digits
- Mesoderm of progress zone with longest exposure to FGF ⇒ develops into distal limb elements
Sonic Hedgehog
Mutations
- Autosomal dominant
- Usually have holoprosencephaly
- See variable expressivity
Fibroblast Growth Factors
9 types of FGF bind to 4 FGFRs
FGFR ⇒ tyrosine kinase receptors
Key role in embryogenesis and fetal development.
Regulates cell proliferation, differentiation and migration.
Acondroplasia
Gain-of-function constitutive activation of FGFR3.
Inappropriate inhibition of chrondrocyte proliferation within the growth plate.
Thalidomide-Induced
Embryopathy
Exposure betweek 4-8 weeks gestation ⇒ high incidence of limb reduction defect.
Disrupts proliferation within the progress zone of limb bud.
Mesoderm only present beneath AER ⇒ long exposure to FGF.
Programmed to form distal limb elements.
See congentitally shortened limbs (phocomelia) with absence of proximal limb elements and well-defined distal limb elements.
