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An overview of human development, focusing on genetic disorders caused by mutations in specific genes. Topics include greig cephalopolysyndactyly, waardenburg’s syndrome, developmental stages, and ways to study genes in development. Realized through mutations in genes like gli3, pax3, and zinc finger genes, these disorders result in cranial and hand abnormalities.
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Greig cephalopolysyndactyly
Polydactyly - extra digits
Syndactyly - webbed digits
Mutation in GLI3 gene on chromosome 7
Zinc finger gene
Cranial, hand abnormalities
Karen B. Avraham, Instructor
Mutation in PAX3 gene on chromosome 2q
Paired-box transcription factor gene
Deafness, white forelock, iris heterochromia
Fruitfly ( Drosophila )
Zebrafish
Worm ( C. elegans )
Mouse
spontaneous
ENU-induced
transgenics
knock-outs
Frog
In situ hybridization
Sections
Whole mount
During establishment of body plan, cells adopt specific cell fates
Cell fates: the capacity to differentiate into particular kinds of cells
Determination: process of commitment to a particular fate
As cells proliferate, decisions are made to specify fate of cells
Cells make developmental decisions in context of decisions made
” by their “neighbors
Totipotent
uncommitted
Single fate
Inner ear
Eye
years ago 15
Description of mutant phenotypes
Microsurgical manipulations of embryos
Today
Combination of genetics and recombinant DNA
techniques
Can now identify protein products contributing to these
developmental events
Can fish out related genes from different organisms
Same basic set of regulatory proteins govern major
developmental events in all higher animals
Genes involved in early development: Transcription factors
Control RNA transcription from DNA template by binding to
specific regulatory DNA sequences
Switch genes on and off by activating or repressing gene
expression
Control many genes involved in segmentation, induction,
migration, differentiation, and apoptosis (programmed cell
death)
Three gene families in vertebrates
homeotic genes
paired box genes
zinc finger genes
Homeosis - replacement of one body
In place of normal antennae, an Ante
causes antennal precursor cells to d
Highly conserved DNA sequence that encodes ~130 aa
First identified in Drosophila
Encode DNA binding proteins
Pax genes identified in mice and humans 8
Mutations in Pax1 cause vertebral malformations in mice
Mutations in Pax3 cause pigmentary abnormalities in mice
Mutations in Pax6 cause small eyes in mice
In humans, mutations in PAX6 cause aniridia (no iris)
In humans, mutations in PAX3 cause Waardenburg’s
syndrome
rearrangements cause rare childhood tumor,alveolar (
) rhabdomyosarcoma
Finger-like projection formed by amino acids
between 2 separated cysteine residues which form
complex with zinc ion
Many DNA binding proteins contain zinc fingers
GLI3 - Greig cephalopolysyndactyly
WT1 (Wilm’s tumor gene)
Increased risk of renal malignancy/ Denyss-
Drash syndrome (abnormal sexual
differentiation and disordered renal
development)
Cells achieve
different roles
through series of “on-
off” decisions
Conditions within
cell allow a master
switch to be regulated
Once master switch
is activated, it sets in
motion a cascade of
“downstream”
regulatory events
In absence of
activation of master
switch, set of default
signals remain in
place
New development
pathway induced
Default developmental
pathway maintained
or
Downstream regulatory
factors induced
Default regulatory
factors operate
Relies on regulation of
one transcription factor
by another
Ratio of X
chromosome to sets of
autosomes (X:A ratio) in
early embryo
establishes whether fly
becomes male or
female
Sexual differentiation
carried out by master
regulatory switch and
several downstream
sex-specific genes
Early
Drosophila
embryo
Repression of
specific -
structural genes
Repression of
specific -
structural genes
X:A = 0.5 X:A = 1
Sx/
ON
Sx/
OFF
tra/
ON
tra/
OFF
dsx-M dsx-F
protein protein
dsx RNA dsx RNA
splice splice
maintenance
Germ cell precursors - pole cells
Genetic studies in Drosophila has led to discovery of genes
involved
Oskar , Nanos , Tudor
Vasa
dependentmember of DEAD-box family of genes encoding ATP-
RNA helicase
required for assembly and function of pole plasm
identified in many animal species, where it is expressed
specifically in germ-cell lineages
C. elegans - P-granules of eggs
Xenopus - germinal granules of eggs
zebrafish
mouse - Mvh
Knock-out
E8.5: the optic vesicle
forms as out-pouching of
forebrain
E9.0: optic vesicle
contacts endoderm of head
E9.5: signals from optic
vesicle induce lens placode
E10.0: lens placode
invaginates to lens pit;
optic vesible inaginates to
create optic cup
E10.5: invagination of
lens pit to form lens vesicle
complete. Lens vesicle
detaches from overlying
ectoderm
E12.5: differentiation of
optic cup into neuroretina
and epithelium
The mouse
Whole mount in situ
hybridization
Pax6 expression in developing
mouse eye
