Genetics of Development: Birth Defects

Question 1

5 cellular processes of development

Answer 1

1. Gene regulation
2. Cell to cell signaling
3. Development of the cell shape/polarity
4. Movement and migration of cells
5. Programmed cell death

Question 2

Developmental fate

Answer 2

A cell travels down a pathway developmentally toward a final fate, losing potential along the way

Question 3

Transcriptional regulatory modules

Answer 3

A group of transcription factors that are expressed together for the same purpose

Question 4

2 classes of transcription factors

Answer 4

1. General

2. Specific

Question 5

Specific and general transcription factors in development

Answer 5

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

Question 6

Rubenstein-Taybi syndrome

Answer 6

Caused by a defect in general transcriptional activator CREBP and affects expression of many genes

Question 7

Function of HOX family transcription factors in development

Answer 7

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

Question 8

Morphogen

Answer 8

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

Question 9

Sonic hedgehog protein (Shh)

Answer 9

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

Question 10

2 functions of the Shh morphogen

Answer 10

1. To organize cells in brain and spinal cord

2. To induce development of posterior limb elements

Question 11

Effects of mutations of Shh

Answer 11

• -Midline defects (ex. failure to develop midface and forebrain)
• -Smith-Lemli-Opitz syndrome

Question 12

Why does a defect in cholesterol biosynthesis affects development?

Answer 12

Shh morphogen needs to interact with cholesterol in order to function properly or it can lead to SLOS

Question 13

Smith-Lemli-Opitz syndrome (SLOS)

Answer 13

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

Question 14

How can statins lead to birth defects?

Answer 14

Statins are cholesterol-lowering drugs that affect the Shh signaling and SLOS-like symptoms due to the importance of cholesterol in Shh signaling

Question 15

How does a cell change shape and polarity?

Answer 15

By rearranging the cytoskeleton and polarizing the secretion of proteins to apical or basal surface of cells

Question 16

How do the polycystin genes regulate polarity development in kidney epithelial cells?

Answer 16

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

Question 17

Polycystic kidney disease

Answer 17

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

Question 18

How is cell migration necessary for the development of the cerebral cortex (and the CNS in general)?

Answer 18

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

Question 19

LIS1 gene

Answer 19

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

Question 20

Lissencephaly

Answer 20

Smooth brain caused by mutation in LIS1 gene

Question 21

5 developmental processes that require programmed cell death (apoptosis)

Answer 21

1. Development of the heart
2. Separation of individual digits
3. Perforation of anal and choanal membranes
4. Establishment of connection between uterus and vagina
5. Development of the immune system

Question 22

Apoptosis in the development of the immune system

Answer 22

Lymphocyte lineages that react to self-components are destroyed by apoptosis and autoimmune diseases can come from failure to destroy these cells

Question 23

Importance of epigenetic programming for cell differentiation

Answer 23

Cells respond to environmental clues by changing shape and polarity

Question 24

Hermaphrodites

Answer 24

Patient has both testes and ovarian tissue

Question 25

Pseudohermaphrodites

Answer 25

Patient has either testes or ovarian tissue but phenotype does not represent genetic sex

Question 26

Sex-determining Region of Y (SRY)

Answer 26

Region of Y-chromosome that is critical for male development

Question 27

Testes Determining Factor (TDF)

Answer 27

Gene located on SRY that initiates testes development

Question 28

How does the Y chromosome drive male development?

Answer 28

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

Question 29

How do chromosomal aberrations lead to sex reversal disorders?

Answer 29

• -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

Question 30

Congenital adrenal hyperplasia

Answer 30

Most common cause for female pseudohermaphrodites with normal ovaries but ambiguous/male genitalia; usually caused by defect in 21-hydroxylase involved in cortisol biosynthesis

Question 31

How does masculinization of female babies occur?

Answer 31

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

Question 32

How does femalization of male bodies occur?

Answer 32

Failure to develop unambiguously male genitalia can come from three different defects:

1. Defect in testes development during embryogenesis
2. Problem in androgen biosynthesis by testes
3. Deficiency in androgen receptor production or signaling by target cells

Question 33

Tumor progenitor cell model

Answer 33

Predicts that errors in epigenetic programming of stem cells during development lay seed for cancer later in life (read p. 584)