Exam 5: Genetics of Development - Principles Flashcards
anterior/posterior axis
first visible structure in embryo
defined by primitive streak, marks groove at which ectodermal cells form 3 germ layers
axes in the developing limb
shoulder-to-fingertip is proximal-distal
thumb-to-fifth-finger is anterior-posterior
dorsum-to-palm is dorsal-ventral
blastocyst
hollow sphere containing group of cells called inner cell mass
16 cell embryo (morula) transforms into blastocyst
chordin
secreted from cells in node and induce dorsal development in concentration-dependent manner
clinical dysmorphology
describes etiology of birth defects and gives valuable clues about underlying abnormality in development process
deformations
result from extrinsic influence on development of affected tissue
defect from outside
lack of amniotic fluid constrains fetus because not enough room to expand - can lead to contractures of limbs
disruptions
destruction of developing tissue
amniotic bands sometimes wrap around developing fetal limbs, choke off their blood supply & tissue is destroyed
ectoderm
develops from epiblast
forms skin and nervous system
embryonal period of development
after fertilization of an egg, begins with 4 cell divisions without cell growth
lasts from week 1 to week 8
endoderm
forms gut and lung epithelium
epiblast
formed from inner cell mass
goes on to form the embryo - upper cell layer
formin and renal aplasia
mutation in formin gene in mice causes renal aplasia in about 20% of mice
All mice were genetically and environmentally identical - means another cause of reduced penetrance
formin mutation can be tolerated - formin mutation does not cause, but rather increases probability for developing renal aplasia
gastrulation
produces primitive streak - first axis of embryo
creates three germ layers - endoderm, mesoderm, and ectoderm
homeobox genes (HOX)
determines patterning (division into segments to define part development) along anterior/posterior axis
family of transcription factors - contain homeodomain, a DNA binding domain
4 HOX clusters on 4 chromosomes
expression of each of genes in cluster correlates with position of cell and timing of expression
Each cell along axis experiences different ration of expression of different HOX genes - code for fate of cell
homeodomain
DNA binding domain contained in homeobox (HOX) genes
inner cell mass
in blastocyst - forms epiblast
isolated anomalies
affect a single body region
usually either sporadic or multifactorial
about 60% of major birth defects
i.e. cleft palate
major anomalies
anomalies with surgical or cosmetic consequences, like cleft lip or amputated limb
minor anomalies
have little impact on well being of patient
give important diagnostic clues about presence of a syndrome
malformations
result from intrinsic abnormality in developmental process
defect comes from within
mesoderm
form bone, muscles, and most internal organs
morula
16 cell embryo
transforms into blastocyst
mosaic phase
begins after gastrulation
loss of a cell in this phase cannot be compensated - will lead to loss of tissue
affects baby - removal of cells for screening needs to be done before this phase
regulative phase
cells functionally equivalent - loss of a part of embryo can be compensated for by neighboring cell
ends with gastrulation
nodal
gene required for formation of primitive streak & later for formation of left/right axis
soluble protein secreted into extracellular space - diffuses through tissue and establishes gradient - NOT a transcription factor (because it can leave the cell)
noggin
protein secreted from cells in the node
induce dorsal development in concentration-dependent manner
polydactyly
extra digits (in hands/feet) mutations interfere with developmental process of limbs originate from defect within affected organ - malformation
primitive streak
defines first axis of embryo, produced by gastrulation
marks groove at which ectodermal cells invade space between epiblast and hypoblast to form 3 germ layer
Robin sequence
causes cleft palate
extrinsic constraint on fetus (from low amount of amniotic fluid) interferes with growth of jaw - small chin
tongue pushes into forming hard palate & blocks formation - forms u-shaped cleft palate
segmental overgrowth
consequence of dysregulation during development - can occur from just one additional cell division per affected cell - loss of control over cell division
sequence
cascade of events
starts from isolated anomaly and leads to multiple malformations - usually sporadic or multifactorial
phenotypes caused sequentially by singe defect
syndrome
affect several body regions and most often display chromosomal or Mendelian inheritance
present when disease phenotypes are caused by single defect simultaneously
situs ambiguus
caused by defects in left/right axis formation
serious condition in which orientation of organs is randomized
usually accompanied by heart defects
situs inversus
caused by defects in left/right axis formation
all of organs are in complete mirror image of where normally found
usually asymptomatic
Sonic hedgehog (Shh)
signaling protein from notochord (precursor of spine) left/right asymmetry caused by asymmetric expressions of this gene - leads to left side expression of nodal, which initiates left-looping of heart tube
Dorsal/ventral axis
specified by noggin and chordin in concentration dependent manner
time of implantation
day 7 to 12
Treacher-Collins Syndrome
autosomal dominant
small jaw, down slanting palpebral fissuers, malar hypoplasia, cleft palate
risk for complications is high and surgery risky
VACTERL association
Vertebral, Anal atresia, Cardiac, Tracheo=Esophagal fistula, Renal and Radial Limb defects)
abnormality that occurs during first 1-4 weeks of development causes multiple major abnormalities in entire embryonic regions
originates from damage to developing mesoderm at 20-25 days after conception
maternal diabetes is a major risk factor
Abnormalities occurring from week 5 to 8
affect specific organs & produce single major anomalies - congenital heart defects
Abnormalities occurring after week 9
have mild effect on individual
What percentage of children are born with a birth defect?
2-3%
What is the percentage of mortality of children with birth defects?
20%, most common cause of infant death in US
What are the most common birth defects
Heart defects, pyloric stenosis, neural tube defects, orofacial clefts, clubfoot
What is the prevalence of heart defects?
1/100 - 1/200 live births
What is the prevalence of pyloric stenosis?
1/300
What is the prevalence of neural tube defects?
1/1,000
What is the prevalence of orofacial clefts?
1/700 - 1/1,000
What is the prevalence of club foot?
1/1,000
Percentage of birth defects with complex/ multifactorial inheritance
50%, no identifiable cause
Percentage of birth defects caused by chromosomal defects
25%
Percentage of birth defects caused by single-gene mutations
20%
Percentage of birth defects caused by non-genetic factors (maternal medication and infections
5%
pre-implantation diagnosis
in morula phase (before mosaic phase) a cell can be removed from embryo and examined for chromosomal aberrations without harming embryo
15 remaining cells develop into normal embryo
5 processes by which cells participate in development
Gene regulation by transcription factors and chromatin modification
Cell-cell signaling, either by direct contact or by secretion of morphogens
Development of specific cell shape and polarity
Movement and migration of cells
Programmed cell death
robustness
countering of factors capable to disturb orderly development
recognized by cell and regulatory mechanisms used
