Molecular Patterning During Development Flashcards
what is intermembranous ossification?
+ formation of bone in fibrous connective tissue (which is formed from condensed mesenchyme cells)
+ process occurs during formation of flat bones e.g. mandible, flat bones of skull
in which week of development do the limbs rotate?
week 7:
+ upper limbs rotate 90° laterally
+ lower limbs
rotate 90 ° medially
what are HOX genes?
during embryonic development they determine body axis and position of limbs along body axis - by acting as morphogen gradients
limb growth is regulated along which 3 axes?
- proximo-distal
- antero-posterior
- dorso-ventral
what is proximo distal development controlled by?
AER - apical ectodermal ridge
how does AER control proximo-distal development?
+ induces underlying tissue to remain as population of undifferentiated rapidly proliferating cells - PROGRESS ZONE
+ as cells move further from AER they begin to differentiate into cartilage and muscle
+ the differentiation results in proximo-distal development
what controls initiation of outgrowth of the forelimb?
+ TBX5 gene
+ FGF-10
what does AER secrete that maintains the progress zone and further development of p-d axis?
+ FGF4
+ FGF8
FGF4 and FGF8
- secreted by AER
- maintains progress zone and further development of p-d axis
what controls the antero-posterior (cranial-caudal) axis?
ZPA - zone of polarizing activity
how does ZPA control a-p axis?
+ cluster of cells near the posterior border of limb form ZPA which regulates the AP axis
+ ensures that thumb grows cranial (anterior) side of limb bud
+ ZPA expresses protein, sonic hedgehog (SHH)
+ ZPA moves distally with AER
what protein does ZPA express?
SHH - sonic hedgehog
what does adding ZPA to limb bud result in?
mirror image duplication of digits
how is dorso-ventral axis controlled?
+ BMPs (in ventral ectoderm) induce EN1
+ EN1 represses WNT7 (restricting its expression to dorsal limb ectoderm)
+ WNT7 induces LMX1 (which specifies the cells to be dorsal)
what is expression HOX gene dependent of?
SHH, FGFs and WNT7a
what is amelia?
complete absence of limbs
what is meromelia?
partial absence of limbs
what is phocomelia?
absence of long bones
what is micromelia?
segments that are abnormally short
what is the term for complete absence of limbs?
amelia
what is the term for partial absence of limbs
meromelia
what is the term for absence of long bones?
phocomelia
what is the term for segments that are abnormally short?
micromelia
what conditions were caused by thalidomide?
+ amelia
+ phocomelia
what causes Holt Oram Syndrome?
TBX5 mutation
what is the result of Holt Oram Syndrome?
+ upper limb deformities
+ heart defects
what is the result of brachydactyly?
short digits
what is the result of syndactyly?
fused digits - failure of apoptosis
what is the result of polydactyly?
extra digits
what is the result of cleft foot?
lobster claw deformity
which defect results in short digits?
brachydactyly
which defect results in fused digits due to failure of apoptosis?
syndactyly
which defect results in extra digits?
polydactyly
which defects results in a lobster claw deformity?
cleft foot
when and where do upper limb buds appear?
- approx. day 24
- between somites C5-T1
when and where do lower limb buds appear?
- approx. on day 28
- between somites L2-S2
when are all major components of limbs present?
by week 8
what does the limb bud consist of?
- core of mesenchyme derived from parietal layer of lateral plate mesoderm
- ectoderm which forms the outer covering of the limb (epidermis)
- ectoderm is thickened at the ‘apex’ of developing limbs to form the Apical Ectodermal Ridge (AER)
what does HOX-8 control?
position of the limb on the long axis of the body
what does TBX5 and FGF-10 control?
initiation of outgrowth of fore limb
steps in AER controlled proximo-distal development
- HOX-8 controls the position of the limb on long axis of body
- initiation of outgrowth of fore limbs is controlled by TBX5 and FGF-10
- AER secretes FGF4 and FGF8to maintain the progress zone and the further development of the proximo-distal axis
- as growth progresses, mesenchymal cells are left behind the advancing ridge (and its influence) and so they begin to differentiate
BMPs
- in ventral ectoderm
- induce EN1
EN1
- represses WNT7, restricting its expression to the dorsal limb ectoderm
- induced by BMPs
WNT7
- induces LMX1
- repressed by EN1
LMX1
- induced by WNT7
- specifies the cells to be dorsal
what do variations in the combinations of HOX genes ensure?
- upper and lower limbs are different TBX5 (upper), TBX4 (lower)
- patterns for the proximal (arm), middle (radius and ulna) and distal (hand) are defined
incidence of limb defects
- limb malformations occur in approx 3.8-1000 live births
- UL abnormalities more common that LL
- limbs defects often associated with other abnormalities affecting CVS, GU system and craniofacial structures
- cause may be hereditary but also by environmental (teratogens)
- affects the progress zone with failures of cell division (weeks 4&5)
what abnormalities of the limbs were seen as a result of thalidomide?
- phocomelia / amelia
- flipper-like arms or legs
- associated with intestinal atresia and cardiac abnormalities
TBX5
mutation leads to defects in limb development (Holt Oram Syndrome)
what are the 2 stages of commitment?
- specification (reversible)
- capable of differentiating autonomously if placed in isolation BUT can be respecified if exposed to certain chemicals/signals - determination (irreversible)
- cell will differentiate autonomously even when exposed to other factors or placed in a different part of the embryo
how does a naive cell become specified?
- intrinsic signal: cell autonomous signal tells cell ‘who it is’
- extrinsic signal: a chemical or molecule int he environment gives the cell spatial information, tells the cell ‘ where it is’
cell fate
- what it will become in the course of normal development
- when a cell “choose” a particular fate, it is said to be determined
progress of a cell during development
- naive
- specified
- determined
- differentiated
competence of a cell
- ability to respond to chemical stimuli
- can lose competence by changes in surface receptor or intracellular molecules
bivalent chromatin
- segments of DNA, bound to histone proteins, that have both repressing and activating epigenetic regulators in the same region
- work to enhance or silence the expression of genes
- both types of regulators are interacting with the same domain at the same time
developmental regulatory genes (transcription factors)
e.g. HOX, SOX, T-box
