Download genetics 10, 193-210

GENETICS CHP 10 (193-198) Developmental Genetics
I.
Intro/Basic Concepts
 2-3% of all liveborn children have a birth defect (100,000/yr)
 leading cause of infant death in US
 Nonhuman model organisms used to study development due to
conservation of genes and pathways across species
o Ex: eyeless in Drosphilia homologous to Pax6 in mice and PAX6 in
humans for eye development
 Conventional to capitalize all letters of names of human genes, only first
letter of names of mouse genes, all lower-case letters for recessive
mutations
 3 major processes in development of embryo
o axis specification- ventral/dorsal, ant/post, med/lat, L/R
specification of polarity
o pattern formation- through induction (cells signaling nearby
cells)
o organogenesis
II.
Paracrine signaling molecules
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Paracrine signaling- when interactions between cells are mediated by
specific proteins that can diffuse across small distances to induce a
response (into space surrounding cells)
4 major families of paracrine signaling molecules
o FGF, Hedgehog, Wingless, and TGF-B
A mutation in genes encoding these signals creates abnormal
communication btw cells
FGF (Fibroblast Growth Factor)
o FGFRs (FGF receptors) consist of single peptide, 3
immunoglobulin-like domains, membrane spanning segment,
and intracellular tyrosine kinase domain
o FGF binds to FGFR phosphorylation activation of tyrosine
kinase domain
o FGFRs common in developing bone- autosomal dominant
disorders of generalized bone growth
o Achondroplasia- disproportionate short limbs
Glycine arginine substitution in transmembrane domain of
FGFR3
Restrains chondrocyte growth and proliferation (ie- too much
inhibition)
o Craniosynostosis- premature fusion of cranial sutures, also
results in misshapen skulls and limb defects
Can be caused by mutations in FGFR1, FGFR2, or FGFR3
Most common is Apert syndrome (mid face hypoplasia, fusion
of digits, FGFR2 mutated)
Hedgehog
First isolated in Droshilia, most common vertebrae homolog is
Sonic Hedgehog (Shh)
o Axis specification, induction of motor neurons within neural
plate, and patterning of limbs
o Primary receptor is transmembrane receptor protein encoded by
Patched
o Patched inhibits fnc of another transmembrane receptor,
Smoothened (encoded by Smo gene)
o binding of Shh to Patched receptor causes disinhibition of
smoothened and activation of signaling cascade to target GLI
family of transcription factors
o Gorlin syndrome- mutation in human PATCHED (PTC), causes
rib anomalies, cysts of jaw, and basal cell carcinomas
Wingless (WNT in humans)
o dorsal/ventral axis (of limbs) and formation of brain, muscles,
gonads, and kidneys
o Code for glycoproteins that bind to frizzled and low-density
lipoprotein (LDL) receptor related protein families
o Homozygous WNT3 mutation causes tetra-amelia (absence of all
4 limbs)
o Abnormal wnt signaling associated with formation of tumors
TGF-B
o Encode for proteins that form homodimers or heterodimers
o Include TGF-B, BMP (bone morphogenic protein), activin, Vg1
families
o Mutation in BMP family, cartilage derived morphogenetic protein
1 (CDMP1) causes skeletal abnormalities
o RTK/MAPK signal transduction pathway regulated specific gene
expression, division, differentiation, and death
Used widely during development
o Noonan syndrome- gain of function of PTPN11 gene, which
encodes a protein that reacts with RTK/MAPK pathway; short
stature, characteristic facial features, webbed neck, congenital
heart disease
o Disruptions of different components of same pathway cause
different malformations but similar clinical features
o Mutation in gene Noggin causes fusion of bones in joints
(mutation of inhibitor of BMP function)
o
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Genetics Chapter 10 pp. 199-205
I. Gene regulation
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Transcription factors: activate or repress sets of genes by regulating transcription of
their DNA. Can lead to a cascade.
Mutations in txn factors have pleiotropic (multiple phenotypes) effects.
Members of a txn factor family usually share a common DNA-binding domain
Examples of txn factor families include…
o HOX, PAX, EMX, MSX (all homeobox families)
o SOX family
Includes SRY (sex-determining region of Y chromosome) gene
SOX10 mutationHirschsprung disease (HSCR)
 HSCR: hypomotility of bowel
 Leads to constipation and distension of bowel
 HSCR can also be feature of OTHER birth defects like Trisomy
21 and Waardenburg syndrome
o Thus, fits multifactorial model of inheritance: caused
by combination of genes AND environmental factoras
o T-box family
Same txn factor often used in different developmental pathways
Extracellular matrix proteins (secreted scaffolding molecules for tissues) also help
mediate development
o Fibrillin-1 and elastin coordinate microfibril assembly of ECM
 Mutation in fibrillin-1  Marfan syndrome
 Mutation in elastin  supravalvular aortic stenosis
 Laminins help form attachments between cells and ECM
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II. Pattern Formation
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Body plan laid out during embryogenesis
Shh txn factor involved in establishing midline
Gastrulation
 Establishment of 3 germ layers: endoderm, mesoderm, ectoderm
 Major structural feature: primitive streak (thickened epiblast)
 Dominated by cell migration
Neurulation + ectoderm
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Formation of neural tube
Mediated by cellular induction (cells of one area influence cells of another area)
controlled by Spemann-Mangold organizer
Neural tissue induced from dorsal ectoderm under control of organizer
Initiates organogenesis
Divides ectoderm into neural tube, epidermis, and neural crest cells
Mesoderm + endoderm
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Mesoderm=notochord, dorsal, intermediate, and lateral mesoderms, and head
mesenchyme
Notochord induces formation of neural tube
Endoderm forms linings of GI tract and respiratory tree
Endoderm-derived structures undergo much BRANCHING, controlled by FGFs
and BMPs
III. Axis Specification
Anterior/Posterior Axis
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Defined by primitive streak (anteriorly has structure called a NODE)
Patterning controlled by homeodomain (made up of homeobox genes)
3’ Hox genes expressed before 5’ Hox genes; Hoxa1 expressed anterior to Hoxa2
o both temporal and spatial colinearity
Dorsal/Ventral Axis
 Noggin and Chordin (secreted from organizer) both dorsalize mesoderm
 BMP-4 ventralizes mesoderm
Formation of Organs and Appendages
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Most of the genes that cause birth defects have prominent roles during this
phase of development
 Genes affecting stages BEFORE organogenesis are possibly lethal
Laterality Defects
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Situs solitus: normal organ arrangement
Situs inversus: mirror image organ arrangement
Situs ambiguus: randomization of organ arrangement
Laterality defects more common in conjoined twins
Cilia play a role in L/R axis
o Dynein defectprimary ciliary dyskinesia
o Most with PCD also exhibit situs inversus
Genetics Ch10 pp. 206-210
A. Formation of organs and appendages
a. Organogenesis occurs after gastrulation
b. Ascertainment bias-harder to identify genes responsible for birth defects
before this stage b/c often fatal
B. Craniofacial development: Majority of craniofacial structures are derived from NC
cells. Fate is specified by homebox genes. Some of these genes isolated by studying
craniosynostosis syndromes.
a. Fore/midbrain Neural crest -> nasal processes, palate, mesenchyme of first
pharyngeal pouch
b. Anterior hindbrain NC -> 2nd p. pouch, stapes, facial cartilage
c. Cervical NC -> 3,4,6 pharyngeal arches (5th degenerates)
d. Fate of NC determined by Hox
i. Hoxa 3 inactivation in mice -> absent thymus, thyroid glands,
vascular malformation
e. Premature fusion of skull bones (craniosynostosis) assoc with other birth
defects, often caused by FGFR mutations or MSX2 (NC apoptosis)
i. Greig cephalopolysyndactyly-mutations in GLI3 (zinc finger tf)
1. C-terminal mutations-affecting both activator and repressor
fcts
ii. Pallister-Hall syndrome: mutations bet zinc finger and microtub
anchor domains
1. Hypothalamic hamartomas, visceral anomalies, posterior
polyd.
iii. Isolated post. Polyd.: mutations of 3’ microtub anchor domain
iv. Rubenstein-Taybi syndrome: loss of fct of Gli cofactor
1. Mental retardation, broad thumbs
C. Box 10-1Animal Models in the Study of Human Development
a. Mouse model construction
i. Embryonic stem cells cultured to be knockout or transgenic
ii. ESS implantd in blastocysts w/ recessive marker
iii. Chimeras born from surrogate: some w/ genetic mods, some without
b. Conditional knockout
i. Condition knocked-out gene to occur only in certain cell type or
specific tissue
ii. Allows study of genes whose knockout would be lethal
D. Development of the Limb: vertebrate limb composed of LP and somitic mesoderm.
Growth and patterning controlled by AER, progress zone, ZPA.
a. r-Fng and Wnt7a direct dorsal mesoderm
i. En-1 (homeobox) blocks Wnt7a expression, directs ventralization
b. Proximal/distal growth controlled by FGFs
i. ZPA -> Shh directs ant/post limb bud axis
c. Holt-Oram syndrome: caused by mutations in TBX5 (t-Box)
i. Atrial septal defect is common; Nkx2-5 also cause the same defects
d. Hox paralogs are partially redundant
i. Ex. Synpolyd. And hand-foot-genital syndrome
E. Organ Formation: reciprocal interactions bet epithelial cells and mesenchyme
mediated by signaling molecules.
a. IPF1 stimulates insulin in beta cells; IPF1 mutation prevents pancreatic
development
b. Dynamic interactions bet mesenchymal and epithelial cells continue to
influence development
i. Tooth development: Bmp-4 -> Msx1. Mutation in MSX1 disrupts
tooth formation
c. Osteoblast differentiation: regulated by Runx2
Disruption: mice w/o ossification. Heterozygotes: ossification abnormalities