Genetics of Development: Birth Defects Flashcards
5 cellular processes of development
- Gene regulation
- Cell to cell signaling
- Development of the cell shape/polarity
- Movement and migration of cells
- Programmed cell death
Developmental fate
A cell travels down a pathway developmentally toward a final fate, losing potential along the way
Transcriptional regulatory modules
A group of transcription factors that are expressed together for the same purpose
2 classes of transcription factors
- General
2. Specific
Specific and general transcription factors in development
General transcription factors: found in thousands of transcriptional complexes (most are in this category)
Specific transcription factors: only function in specific cells at a specific time
Rubenstein-Taybi syndrome
Caused by a defect in general transcriptional activator CREBP and affects expression of many genes
Function of HOX family transcription factors in development
Important for patterning along anterior-posterior axis and genes 11 and 13 are involved in development of distal pole of limbs; defects in HOXA13 and HOXD13 disturb development of fingers and toes
Morphogen
Substance that is secreted by cells in one part of the embryo; gradient can be established by diffusion through developing tissues – cells initiate different developmental programs based on concentration
Sonic hedgehog protein (Shh)
Secreted from notochord and floorplate of developing neural tube to help organize cells in brain and spinal cord; secreted from zone of developing limb to induce development of posterior limb elements
2 functions of the Shh morphogen
- To organize cells in brain and spinal cord
2. To induce development of posterior limb elements
Effects of mutations of Shh
- -Midline defects (ex. failure to develop midface and forebrain)
- -Smith-Lemli-Opitz syndrome
Why does a defect in cholesterol biosynthesis affects development?
Shh morphogen needs to interact with cholesterol in order to function properly or it can lead to SLOS
Smith-Lemli-Opitz syndrome (SLOS)
Autosomal recessive disorder affecting 1/20,000-40,000 that leads to congenital malformations due to an impairment in Shh signaling by a defect in cholesterol biosynthesis
How can statins lead to birth defects?
Statins are cholesterol-lowering drugs that affect the Shh signaling and SLOS-like symptoms due to the importance of cholesterol in Shh signaling
How does a cell change shape and polarity?
By rearranging the cytoskeleton and polarizing the secretion of proteins to apical or basal surface of cells
How do the polycystin genes regulate polarity development in kidney epithelial cells?
Developing kidneys must develop a polarity for apical and basal faces of the cell by sensing fluid flow; cells can be made incapable of this when there are mutations in the polycystin genes, causing cell proliferation and cysts
Polycystic kidney disease
Types 1 and 2 are caused by development of kidney cysts due to overgrowth of kidney duct caused by failure of epithelial cells to stop dividing
How is cell migration necessary for the development of the cerebral cortex (and the CNS in general)?
Cells must migrate through developing embryo in order to form CNS; neuronal stem cells divide and form neuronal precursor cells that migrate outward along a scaffold of glial cells
LIS1 gene
Mutation on this gene interferes with cell migration pattern, which thickens the cerebral cortex, causes it to have undefined cell layers, and makes it smooth – causes severe mental retardation
Lissencephaly
Smooth brain caused by mutation in LIS1 gene
5 developmental processes that require programmed cell death (apoptosis)
- Development of the heart
- Separation of individual digits
- Perforation of anal and choanal membranes
- Establishment of connection between uterus and vagina
- Development of the immune system
Apoptosis in the development of the immune system
Lymphocyte lineages that react to self-components are destroyed by apoptosis and autoimmune diseases can come from failure to destroy these cells
Importance of epigenetic programming for cell differentiation
Cells respond to environmental clues by changing shape and polarity
Hermaphrodites
Patient has both testes and ovarian tissue
Pseudohermaphrodites
Patient has either testes or ovarian tissue but phenotype does not represent genetic sex
Sex-determining Region of Y (SRY)
Region of Y-chromosome that is critical for male development
Testes Determining Factor (TDF)
Gene located on SRY that initiates testes development
How does the Y chromosome drive male development?
Genetic sex of embryo is determined by presence or absence of Y-chromosome; SRY/TDF on Y lead to testes, which produce androgens to develop male external genitalia
How do chromosomal aberrations lead to sex reversal disorders?
- -If SRY is deleted on the Y-chromosome, embryo develops into female with XY karyotype
- -If SRY is translocated to the X-chromosome, embryo develops into male with XX karyotype
Congenital adrenal hyperplasia
Most common cause for female pseudohermaphrodites with normal ovaries but ambiguous/male genitalia; usually caused by defect in 21-hydroxylase involved in cortisol biosynthesis
How does masculinization of female babies occur?
Congenital adrenal hyperplasia (CAH) causes a defect that leads to block in cortisol synthesis, shuttling intermediates into androgen synthesis pathway; females have high androgen levels and ambiguous/male genitalia
How does femalization of male bodies occur?
Failure to develop unambiguously male genitalia can come from three different defects:
- Defect in testes development during embryogenesis
- Problem in androgen biosynthesis by testes
- Deficiency in androgen receptor production or signaling by target cells
Tumor progenitor cell model
Predicts that errors in epigenetic programming of stem cells during development lay seed for cancer later in life (read p. 584)
