Unit 3.L2-Developmental Signaling & Molecular Basis of Birth Defects

Question 1

Classification of the causes of birth defects:

• How many of the US births are infant deaths due to birth defects?
• What occurs to most embryos by 6 weeks in the early embryonic stage?

Answer 1

• Infant deaths due to birth defects:>20% of births in the US
• Most embryos spontaneously abort by 6 weeks in early embryonic stage” (~15% pregnancies)

Spontaneous abortion occurs in ~15% of pregnancies when the mother knows she’s pregnant

Question 2

What factors can cause birth defects and include the percentages?

Answer 2

• Genetic factors: Chromosomal abnormalities account for ~50% of spontaneous abortions (of 15% of pregnancies)
• Environmental factors: Drugs and Viruses (7-10%)
• Multifactorial inheritance: Genetic & Environmental factors (20-25%)
• Unknown causes: 50-60%:

Question 3

What normally occurs during the first 2 weeks of development? What birth defects can occur?

Answer 3

• Normally, the period of dividing zygote, implantation, and bilaminar embryo
• Birth Defects: Embryonic death & spontaneous abortion

Question 4

What period is the most suspectible period to birth defects? What are the major birth defects that can occur during the this time?

Answer 4

3-8 Weeks (Main Embryonic Period): Most Susceptible Period

• Major (congential) birth defects:

1. Amelia/limb defects
2. Cardiac defects (TA, ASD,VSD) (Heart)
3. Neural tube defects
4. Spina bifida cystica
5. Eye defects (Microphthalmia, cataracts, glucoma)
6. Mental retardation
7. Amelia/Meromelia (Upper&Lower limbs)
8. Cleft lip (Upper lip)
9. Low-set malformed ears & deafness
10. Enamel hypoplasia and staining
11. Cleft Palate
12. Masculinazation of female genitalia

Question 5

What birth defects occurs in the Fetal Period (9-38 wks)?

Answer 5

9-38 Wk Less Sensitive to Teratogens

• Minor Functional defects
• Palate, teeth, genitalia anomalies

Question 6

When is the development of the embryo most easily disrupted?

Answer 6

Development of the embryo is most easily disrupted during tissues & organs formation

Question 7

What is the critical period for brain development? What happens in this period?

Answer 7

Critical period for brain development is long (3-16 weeks) and starts early; thus, maximum defects are observed in the brain

Question 8

When does the heart develop? What occurs during this period?

Answer 8

Heart develops in the 3-8 weeks / organogenetic period; major defects occur in this period.

Question 9

When do pregnant ladies must remain the most careful?

Answer 9

Pregnant lady must remain most careful: first 3-16 weeks (mental retardation can occur till 16 weeks)

Question 10

For the organ listed below what are the number of incidence of birth defects that could occur:

• Brain
• Heart
• Kidneys
• Limbs
• All other
• Total

Answer 10

• Brain: 10 in 1000
• Heart: 8 in 1000
• Kidneys: 4 in 1000
• Limbs: 2 in 1000
• All other: 2 in 1000
• Total: 30 in 1000

Question 11

What does the birth defect types that arise depend on?

Answer 11

The type of birth defect depends on the tissues & organs most susceptible at the time of exposure to the teratogen (substances that cause congenital disorders in a developing embryo or fetus)

Question 12

What are common teratogens that cause birth defects and what defects do they cause?

Answer 12

1. High levels of ionizing radiation:

• CNS defects (brain & spinal cord)
• Eye defects

2. Rubella virus infection:

• Eye defects (glaucoma & cataracts)
• Deafness
• Cardiac defects

3. Thalidomideinduces defects:

• Limb/digits
• Cardiac
• Kidney

Risk of Birth Defects Increases during the Early Organogenetic Period

Question 13

How much birth defects are caused by mutant genes?

Answer 13

Mutant genes cause apporximately one-third of all birth defects

• Sex-chromosomes
• Autosomal

Question 14

What causes chromosomal aberrations (non-disjunction)?

Answer 14

Malfunctioning in mitosis or meiosis causes chromosomal aberrations

Question 15

Aberrant Chromosome Numbers at Birth

What is Aneuploidy? How common is it? Include example.

Answer 15

• Chromosome number not an exact multiple of the haploid number of 23. Could be 45 or 47
• Most common; 3-4% of all clinical pregnancies
• Example: Down Syndrome (46+1extra)

Question 16

What is Polyploidy? Include example. How can it be caused?

Answer 16

• Multiple of the haploid number of 23 other than 46 (diploid)
• Example: 3 X 23 = 69 is common
• Cause: When you get two sperms that fertalize egg

Question 17

What is Hypodiploidy? Include examples.

Answer 17

• Decrease in One or more chromosome from 46.
• Example: 45, as in X0 (Turner syndrome; 1% survive)

Question 18

What is Hyperploidy? Include examples.

Answer 18

• More than 46 chromosomes
• Example: 47 or more, as in trisomy 21 or Down Syndrome

Question 19

What is Monosomy? What is the normal life expectancy? Include examples.

Answer 19

• Neonates missing a chromosome usually die
• 99% of embryos lacking a sex chromosome
• Example: 45,X; abort spontaneously. Those who survive have Turner’s Syndrome

Question 20

What leads to nondisjuction during maternal or paternal gametogenesis?

Answer 20

A failure of a chromosomal pair or two chromatids of a chromosome to disjoin at meiosis leads to “nondisjunction during maternal or paternal gametogenesis.

Question 21

What is the result of nondisjuction during maternal or paternal gametogenesis?

Answer 21

Extra chromosomal pair or chromatids in one daughter cell & missing chromosome in other daughter cell

Question 22

What is Trisomy 21 (Down Syndrome)? What is the number of incidence? Down syndrome represents how many institutionalized individauls w/ severe mental retardation?

Answer 22

• Down Syndrome (trisomy 21): Meiotic nondisjunction of autosomes; three chromosome copies in 21st chromosome pair ; thus called trisomies; the most common chromosomal abnormality
• 1 in 800
• Down syndrome represent 10% to 15% of institutionalized individuals with severe mental retardation.

Question 23

What is the life expectancy of people w/ Down Syndrome? What are physical apperances present?

Answer 23

• Life expectancy : 55-60 years
• Physical appearances:
  1. Flat facial profile and an upward slant to the eye
  2. Short neck
  3. Abnormally shaped ears
  4. Single, deep transverse crease on the palm of the hand

Question 24

What causes Trisomy 21 (Down Syndrome)? In a decade how many infants wiill have Trisomy 21 (to women older than 34). What occurs in ~5% of infants?

Answer 24

• Errors in meiosis with increasing maternal age cause trisomy 21
• In a decade, 39% of infants will have trisomy 21 to women older than 34
• Chromosomal Translocation or Mosaicism occurs in ~5% of infants

Question 25

What is Mosaicism?

Answer 25

A condition in which two or more cell types contain different numbers of chromosomes (normal and abnormal), leading to a less severe phenotype, with normal IQ.

Question 26

List the Incidence of Down Syndrome at the maternal ages below:

• 20-24
• 25-29
• 30-34
• 35
• 37
• 39
• 41
• 43
• 45+

Answer 26

• 20-24: 1 in 1400
• 25-29: 1 in 1100
• 30-34: 1 in 700
• 35: 1 in 350
• 37: 1 in 370
• 39: 1 in 140
• 41: 1 in 85
• 43: 1 in 50
• 45+: 1 in 30

Question 27

What are physical signs of Down Syndrome? (13)

Answer 27

• Decreased muscle tone at birth
• Excess skin at the nape of the neck
• Flattened nose
• Upward slanting eyes
• Small ears
• Small mouth
• Wide, short hands with stubby fingers
• Widely separated 1st & 2nd toes
• Separated joints between skull bones
• Single crease in the palms
• White spots on the pigmented eye.
• Extra loops of prints on fingers
• Short incurved 5th finger

Question 28

What is Edwards Syndrome (Trisomy 18)? How common in US births? What are side effects present?

Answer 28

Edwards Syndrome (trisomy 18): 3 pair on chromosome 18
1:8000 births in the US

• Side Effects:
  1. Severe Malformations
  2. Die early in infancy
  3. Spina bifida
  4. Facial clefts
  5. Dysmorphic features
  6. Severe Developmental delay
  7. Congenital Heart Defects
  8. Microcephaly
  9. Short neck
  10. Prominent sternum
  11. Wide nipples
  12. Dysplastic ears
  13. Clenched hands with overlapping digits
  14. Micrognathia (undersized lower-jaw)

Question 29

What is a major side effect of trisomy 18 (Edwards Syndrome) ?

Answer 29

Micrognathia (undersized lower-jaw)

Question 30

What is Patau Syndrome (Trisomy 13)? How common in US births? What are the side effects present?

Answer 30

Patau Syndrome (trisomy 13): 3 pairs on chromosome 13
1:8000-12,000 among live births in the US

• Side Effects:
  1. Severe abnormalities & malformations
  2. Death very early in life (median survival 2.5 days)
  3. Microphthalmia
  4. Extra fingers or toe
  5. An opening in the lip (may or may not have a cleft lip)
  6. Weak muscle tone (hypotonia)

Question 31

What is the cause of Trisomy 13 (Patau Syndrome)? What has reduced incidence?

Answer 31

• Cause: Idiopathic; increases with mother’s age
• Prenatal examination, elective abortions & loss of a child through miscarriages have reduced incidence.

Question 32

What is Reciprocal translocation? What does it cause?

Answer 32

If two nonhomologous chromosomes exchange pieces, it is called a reciprocal translocation. Translocation does not necessarily cause abnormal development

Structural chromosomal abnormality

Question 33

What are Balanced translocation carriers? What is the caveat concerning balanced translocation?

Answer 33

• Persons with reciprocal translocation but no phenotype
• Caveat: But their gametes have abnormally translocated chromosomal regions which may show up in the progeny

Question 34

How many infants with down syndrome have translocation trisomies?

Answer 34

3-4% of infants with Down Syndrome have “Translocation trisomies”; the extra chromosome 21 is attached to another chromosome; not necessarily to the pair of chr. 21

Question 35

What is Chromosomal Deletions?

Answer 35

When a chromosome breaks, part of it may be lost; called deletion

Question 36

What is the chromosomal deletion that causes Cri du chat syndrome? What are the diagnosis present?

Autosomal Deletions

Answer 36

• A partial terminal deletion from the short arm p of chromosome 5 (5p) causes the cri du chat syndrome (X,Y,5p)
• Cri du chat syndrome diagnosis:
  1. Infants have a weak cat-like cry
  2. Microcephaly
  3. Severe mental deficiency
  4. Congenital heart disease
  5. Hypertelorism (increased interorbital distance)

Karyotype of the child shows a terminal deletion (5p) of the short arm p of. chromosone 5

Question 37

What is the chromosomal deletion that causes Turner Syndrome? What are the clinical presentations?

Answer 37

• Missing Sex Chromosome (monosomy X female):
  Turner Syndrome (45,XO) due to chromosomal nondisjunction
• Clinical Presentations:
  1. Short Stature
  2. Webbed neck and prominent ears
  3. No sexual maturation
  4. Broad chest (widely spaced nipples)
  5. Lymphedema in hands/feet

Question 38

What are common trisomy of Sex Chromosomes? What sex do they affect? Number of incidence? Usual characteristics?

Answer 38

47, XXX

• Female
• 1 in 1000
• Normal in apperance; usually fertile; 15% to 25% are midly mentally deficient

47, XXY

• Male
• 1in 1000
• Kinefelter syndrome: small testes, hyalinization of seminferous tubules; aspermatogenesis; often tall w/ disproportionately long lower limbs. Intelligence of siblings less than normal. Approx. 40% of thes males have gynecomastia

47, XYY (Jacob’s Syndrome)

• Male
• 1 in 1000
• Normal in apperance, usually tall, and often exhibit aggressive behavior

Question 39

How often are gene mutants seen in birth defects? What occurs d/t gene mutations?

Answer 39

• Gene mutations seen in 7-8% of birth defects: Loss of gene function is permanent & heritable
• Most mutations are deleterious or lethal, follow Mendelian laws of inheritance; thus, predictable in families
• Examples: Autosomal Dominant inheritance, Autosomal Recessive Inheritance

Question 40

What causes the Autosomal Dominant birth defect Achondroplasia? What clinical features are present?

Answer 40

• G-to-A transition mutation in FGFR3 (fibroblast growth factor receptor 3) gene on chromosome 4p
• Clinical features: Short stature, short limbs & fingers, bowed legs, large head, a prominent forehead, and a depressed nasal bridge

Question 41

What is needed for phenotype of Autosomal Recessive Inheritance? List examples

Answer 41

• Need both copies of gene mutated (Homozygous mutations) →phenotype
• A parent (Heterozygous defective gene ) is a carrier with no phenotype
• Examples:
  1. Congenital Suprarenal (Adrenal) Hyperplasia
  2. Microcephaly

Question 42

What causes the Autosomal Recessive birth defect Congenital Suprarenal (Adrenal) Hyperplasia? What clinical features are present?

Answer 42

• Excessive androgens due to congenital adrenal hyperplasia
• Clinical features: Causes masculinized external genitalia (enlarged clitoris & fused labia majora)

Question 43

Sex-chromosome Aberration

What is Fragile X Syndrome? What disorders is it associated with? What defect causes this syndrome?

Answer 43

• A common X-linked disorders (1:4000 in males) associated with mental impairment & Autism spectrum disorders (ASD)
• Cause: Chromosome lesion at Xq27.3 and expansion of CGG nucleotide repeats in a specific region of theFMR1(Fragile X Mental Retardation 1) gene required for cognitive development
  .

Question 44

Fragile X Syndrome

What protein does the FMR1 gene make? What is the protein function in the brain? How does Fragile X Syndrome affect this gene?

Answer 44

• FMR1 gene makes a protein, FMRP (in brain, testes, & ovaries).
• BRAIN→development of connections between nerve cells (synapses) & in synaptic plasticity. FMRP regulate synaptic plasticity for learning & memory
• Expansion to >55-200 CGG repeats; gets C-methylated and the gene is silenced

Need up to 55 CGG to have Fragile X Syndrome

Question 45

How does Fragile X Syndrome affect male and females? What clinical features occur?

Answer 45

• Males have severe disease (only one X-chromosome)
• Females have a milder disease
• For males- a long face & prominent ears. Females mild learning disability. Both have strabismus

Question 46

How is embryogenesis regulated? What can lead to birth defects during embryogenesis?

Answer 46

• Embryogenesis is regulated by multiple cell-signaling cascades
• Aberrant cell-signaling leads to birth defects

Question 47

What are the three modules of Cell signaling Pathway?

Answer 47

1. Reception (Receptors)
2. Transduction (signal-transduction pathway)
3. Response (Activation of cellular responses)

Question 48

What are the needs and consequences of Cell Signaling in Development? (7)

Answer 48

1. Rapid response
2. Rapid amplification of response
3. Rapid death (Apoptosis for sculpting/shaping)
4. Temporal regulation
5. Tissue specificity
6. Differentiation – dedifferentiation
7. Maintenance of stem cells

Question 49

What is the language of signaling? List the examples

Answer 49

Specific Combinations of extracellular signal control “cell-decisions” in the Embryo

• EXAMPLES:
  1. To survive
  2. To divide
  3. To secrete
  4. To move
  5. To size
  6. To shape
  7. To position
  8. To secrete
  9. To time
  10. To mature
  11. To defend
  12. To differentiate/dedifferentiate
  13. To change color
  14. To die

Question 50

What are the major types of signals for the cells?

Answer 50

• Local signals (Autocrine/Paracrine)
• Hormonal signals (Hormones/Endocrine)

Question 51

For Local signals (Autocrine/Paracrine):

• What is the distance?
• What is it dependent on?
• What cells are affected?
• Example

Answer 51

• Short-distance
• Contact dependent (autocrine)
• Affect the cells that produce them (autocrine)
• Affect nearby cells (diffuse) (paracrine)
• Synaptic

Autocrine (same cell)
Paracrine (adjacent cells-5,10,20 cells down)

Question 52

For Hormonal signals (Hormones/Endocrine):

• What is the distance?
• What cells are affected?
• What is used for distribution?

Answer 52

• Long-distance
• Multicellular organisms
• Use circulatory system for distribution

Question 53

What are the four major ways of cellular signaling during Embryogenesis?

Answer 53

1. Contact-dependent (Juxtacrine)
2. Paracrine
3. Synaptic (Paracrine)
4. Endocrine

Question 54

Where do Autocrine and Paracrine signaling bind to?

Answer 54

• Autocrine signals bind to receptors on the same cell that secret them
• Paracrine signals bind to receptors on nearby cells

NOTE: cells without receptors for a particular signal do not respond to that signal

Question 55

What are the main Endocrine signals in early development? (3) How are circulating signals transported?

Answer 55

1. Insulin-like growth factor 2 (IGF-2)
2. Growth hormone (GH)
3. Parathyroid-hormone-related protein (PHRP)

• Circulating signals are transported by the circulatory system and bind to receptors on distant cells

Question 56

What is the Cell’s signaling cascade during intracellular signaling? (5)

Answer 56

1. Stimulus (Ligand as Signal)
2. Stimulus sensing (Receptors)
3. Communication (Adaptors)
4. Information processing (Transducers)
5. Decision making (Effectors)

Question 57

Membrane & Intracellular Receptors

What do receptors bind? Receptors are highly what? What is the typical signal molecule concentration? How many human genes encode for receptors?

Answer 57

• Receptors bind signaling molecules (ligands)
• Receptors are highly sensitive and specific
• Typical signal molecule concentration <10^8 M
• >1500 human genes encode receptors

Question 58

Membrane & Intracellular Receptors

What are the 2 types of receptors and where are they located?

Answer 58

• Cell surface-Most receptors (hydrophilic-goes through blood)
• Intracellular-Some receptors (hydrophobic-requires carrier protein)
• Receptors: For light, gas or chemicals

Question 59

What are the 2 types of Developmental Signaling and include examples?

Answer 59

1. Intercellular Communication

• Gap junctions
• Cell Adhesion Molecules

2. Morphogens

• Extrinsic Chemical Gradients for Cell-Signaling

Question 60

Intercellular Communication

What makes up each Gap Junction?

Answer 60

Two hemichannels (connexons)

Question 61

Intercellular Communication

What does each hexameric connexon consist of?

Answer 61

Consist of 6 connexin subunits

6 connexin make 1 Hemichannel (Connexon)

Question 62

Intercellular Communication

Each Connexin (Cx) molecule comprises of?

Answer 62

• 4 transmembrane domains + 2 Extracellular domains (N-terminus & C-terminus)→Cytoplasmic/intracelluar

Question 63

Humans have how many connexin-type molecules? What are the different gap junctions that can arise and why?

Answer 63

• Humans have ~20 Connexin-type of molecules
• Gap junction combinations:
  1. Homotypic Connexons
  2. Heterotypic Connexons
  3. Homomeric Connexin
  4. Heteromeric Connexin
• For Cellular & Tissue Functional diversity

Note: -typic (different cell), -meric (same cell)

Question 64

What are the Protein Elements of a Generic Connexin? (5)

Answer 64

1. The Intracellular N-terminus (NH2)
2. TWO Extracellular Loop (EL) domains
3. FOUR Transmembrane (TM ) domains
4. ONE Cytoplasmic Loop (CL) domain
5. The Intracellular C-terminus (CT)

Question 65

What is the function of Gap Junction Intercellular Communication (GJIC) in development?

Answer 65

Early development: GJIC→ Rapid distribution of (ions + small molecules, calcium, second messenger, ATP, molecules <1kDa) essential for regionalization before distinct boundaries/compartments formed in in embryo

Question 66

What is the function of Bound Connexons (Gap Junction) in the nervous and cardic systems?

Answer 66

GJIC establish electrical cell coupling (“electrical” synapse)

Question 67

What are the connexins for the organs/tissues listed below:

• Heart, brain
• Heart, pancreas
• Myelin
• Pancreas, brain

Answer 67

• Connexin Cx43 (heart, brain)
• Cx45 (heart, pancreas)
• Cx32 (myelin)
• Cx36 (pancreas, brain)

Question 68

What is the function of unbound connexons (hemichannels; connexin molecule)?

Answer 68

Exchange ions/small molecules between Cytoplasm←→ extracellular matrix

Question 69

Cogential Defects d/t different Gap Junction

What defect causes Keratitis-ichthyosis-deafness syndrome (KID)? What are the clinical presentations that occur d/t this syndrome?

Answer 69

• Aberrant hemichannel activation through GJB2 or Cx26
• Clinical Presentations:
  1. Corneal inflammation & increased sensitivity to light
  (photophobia)
  2. Keratitis (thick skin; dry and scaly)
  3. Hearing loss
  4. Susceptible to Squamous Cell Carcinoma of the skin (d/t skin continuously slopped off)

Question 70

Cogential Defects d/t different Gap Junction

What defect causes X-linked Charcot-Marie-Tooth disease (CMT-Disease)? What does this disease cause? How common is it? What are the clinical presentations that occur d/t this syndrome?

Answer 70

• Congenital Mutations in CX gene GJB1 or Cx32 (myelin)
• “Hereditary motor and sensory neuropathy” (HMSN)
• Most common hereditary peripheral neuropathy (1:2,500 births in the US)
• Clinical Presentations:
  1. Loss of touch & therefore, wasting of muscles
  2. Foot abnormalities:
• High arches
• Flat feet
• Curled toes (hammer toes)

Question 71

Intercellular Communication

What are Cell Adhesion Molecules (CAMs)? What is their function? What is the structure?

Answer 71

• CAMS: Large extracellular protein domains
• Function: Interact with extracellular matrix (ECM), Adhesion molecules on neighboring cells
• Structure: (Long Transmembrane Segment + Short Cytoplasmic Domain)→regulate intracellular signaling

Other examples: NCAM (neural cell), PCAM (platelet), ICAM (immunoglobin)

Question 72

Intercellular Communication

What are two classes of Cell Adhesion Molecules (CAM) present in Embryo Development?

Answer 72

1. Cadherins
2. Immunoglobulin superfamily of cell adhesion molecules (>700 members)

Question 73

What is the structure of Cadherin? What is the extracellular binding sites and domain numbers? Where does it bind to intracellularly? What does the complex link to?

Answer 73

Cadherin Structure (Homodimer)

1. Cadherin (Extracellular):

• 4-Calcium-binding sites X 2 = 8 binding sites
• 5-Repeat-domains (extracellular cadherin domains) X 2 = 10 Repeats

2. Cadherin (Intracellular)→binds (p120 catenin + β-catenin/α-catenin)
3. The complex links to actin cytoskeleton

Question 74

What is the function of E-cadherin? What does a loss of E-cadherin cause?

Answer 74

• Function: E-cadherin maintains epithelial phenotype.
• Loss of E-cadherin cause EMT, which is required for the formation & movement of neural crest cells

Question 75

Immunoglobulin superfamily of cell adhesion molecules

What is the structure of the Neural cell-adhesion molecule (NCAM)? What transmits the Intracellular signaling?

Answer 75

1. 5 Immunoglobulin repeats + 2 fibronectin type III domains
2. 5th Ig-repeat has polysialylation (PolySialic acid; PSA), which decreases the adhesiveness of the NCAM molecule.
3. Intracellular signaling is transmitted by the Adaptors: FYN /FAK kinases

Question 76

What are the functions of Neural cell-adhesion molecule (NCAM)?

Answer 76

1. PSA decreases the adhesiveness of NCAM and facilitates Neural Cell Migration during the formation of neural structures
2. NCAM regulates neurite
   outgrowth, axonal path finding, neural cell survival, and plasticity

Question 77

What are Morphogens and include examples?

Answer 77

Extrinsic Chemical Gradients for Cell-Signaling

• Retinoic Acid
• TGF-β)/BMPs (Transforming Growth Factor-β/Bone Morphogenetic Proteins)
• Hedgehog(Sonic Hedgehog; SHH)
• WNT/β-Catenin Pathway

Question 78

What proteins/factors are part of the TGF-β Superfamily?

Answer 78

• TGF-β
• BMPs
• Activin
• Nodals

Question 79

What are the three TGF-β Ligand isoforms?

Answer 79

• TGF-β1
• TGF-β2
• TGF-β3

Question 80

Explain the activation pathway of TGF-β + hetertetramic (4-subunit) complex. Include what causes inhibition.

1. What structures make the transmembrane ligation?
2. What domain is activated?
3. What is phosphroylated?
4. Which structures enter the Nucleus?
5. What strcuture binds promoter DNA? What does it activate after binding?
6. What blocks gene activation?

Answer 80

1. 2TβR-I-inactive + 2TβR-II-active (P)→ transmembrane ligation
2. Intracellular Serine-Threonine Kinase Domain is activated
3. Phosphorylates intracellular receptor-associated SMAD proteins (R-SMADs2/3)
4. (R-SMADs) + Common-partner (Co-SMADs)/SMAD4 →Enters Nucleus
5. (R-SMADs)/Co-SMAD –bind promoter DNA→activate developmental genes
6. For Inhibition: I-SMADs (SMAD-6 & SMAD-7) block gene activation.

Question 81

What is the developmental function of TGF-β?

Answer 81

TGF-β instruct dorsoventral patterning, cell fate decisions, formation of specific organs, including the nervous system, kidneys, skeleton & hematopoiesis

Question 82

Sonic Hedgehog Signaling (SHH)

What occurs in the Repressed SHH Pathway (SHH not present)?

Answer 82

1. Patched (Ptc)→ constitutively Repress Smoothened (Smo) receptor→ Smo cannot signal downstream
2. SuFu (Suppressor of Fused) cannot suppress Fused (Fu)
3. [Costal 2 (Cos2) + Fused (Fu) + Gli ]→ Gli ready for phosphorylation.
4. Kinases (CK1 + GSK3 +PKA) phosphorylate/activate→ Gli-R
5. Active Gli-R→Represses transcription of SHH-genes in development

Question 83

Sonic Hedgehog Signaling (SHH)

What occurs in the Activated SHH Pathway?

Answer 83

1. SHH is cleaved + [C-term Cholesterol]+ [N-term Palmitate]
2. Shh-Chol ligand inhibits the PTC receptor→→Smo is active
3. Active Smo→ Suppress Fu in a complex→ Activats Gli (Gli-A)
4. [Gli-A + CBP] bind promoters→ Activate SHH-target genes in development

SHH Processing→N-Shh

• N-term: Palmitate
• C-term: Cholesterol

Question 84

Sonic Hedgehog Pathway (SHH) defects cause what?

Answer 84

• Perturbations in SHH-PTCH-GLI signaling pathway lead to several birth defects.
• SHH is expressed in the notochord, the neural tube floor plate, the brain, developing limbs and the gut. Sporadic/inherited SHH gene mutations leads to holoprosencephaly

Question 85

What is Holoprosencephaly?

Answer 85

• Abnormal CNS septation, facial clefting, single central incisor, hypotelorism, or a single Cyclopic eye (Cyclopia)
• Failure of cleavage of the prosencephalon (rostral neural tube) into right and left cerebral hemispheres, telencephalon and diencephalon, and olfactory bulbs and optic tracts.

Question 86

What does SHH mutation cause?

Answer 86

• Holoprosencephaly, a congenital brain defect; two fused cerebral hemispheres
• Anophthalmia or cyclopia

Question 87

What does Teratogen cyclopamine inhibits and what are its effect? What can the consumsion of Corn lily cause?

Answer 87

• Teratogen cyclopamine inhibits Smoothened→activates GLI-R & abrogates SHH signaling
• Consuming Corn lily→Cyclopia

Corn lily (Veratrum Californicum) or Vetch Weed
Alkaloid: Cyclopamine/11-deoxyjervine

Question 88

What can an inborn error of cholesterol synthesis cause?

Answer 88

Inborn error of cholesterol synthesis→ abrogates SHH signaling→ Smith-Lemli-Opitz syndrome → Holoprosencephaly

Question 89

What does GLI3 mutations cause?

Answer 89

GLI3 mutations→ Autosomal dominant polydactyly syndromes (Greig cephalopolysyndactyly syndrome)

Question 90

The WNT/β-Catenin Pathway signaling is complex. What are the three signaling pathways?

Answer 90

1. The classical/canonical β-catenin–dependent pathway
2. Wnt/calcium pathway
3. Planar Cell Polarity (PCP) pathway

Question 91

What occurs in the Inactive Classical WNT/β-catenin pathway?

Answer 91

Absence of Wnt-ligand
1. Frizzled (FZD) Receptor & LRP5/6 Co-receptor do not interact & cannot phosphorylate Dishevelled (DVL) →Inactive
2. β-catenin is continuously phosphorylated (P) by a multiprotein complex, which sends it for degradation→ Gene expression Off

Multiprotein complex: APC (Adenomatous polyposis coli), GSK3 (Glycogen Synthase kinase 3) & Axin

Question 92

What occurs in the Active Classical WNT/β-catenin pathway?

Answer 92

Wnt Present

1. WNT binds to FZD receptor & interacts with LRP-Coreceptor
2. Dishevelled (DVL) is phosphorylated (P-DVL) & activated
3. P-DVL disrupts the multiprotein complex, releasing stable β-catenin, which enters the nucleus→ Developmental Gene Expression on

Multiprotein complex: APC (Adenomatous polyposis coli), GSK3 (Glycogen Synthase kinase 3) & Axin

Question 93

What is the multiprotein complex in the Classical Wnt/B-catenin pathway?

Answer 93

• APC (Adenomatous polyposis coli)
• GSK3 (Glycogen Synthase kinase 3)
• Axin

Question 94

What diseases/disorders can arise because of Dysregulated WNT Signaling?

Answer 94

Several Developmental Disorders:
1. Williams-Beuren syndrome
2. Osteoporosis-pseudoglioma syndrome

Tumors & cancers
3. Medulloblastoma in Kids
4. Colorectal Cancer
5. Turcot syndrome

Question 95

Dysregulated WNT Signaling & Diseases

What causes Williams-Beuren syndrome?
What are the symptoms?

Answer 95

• Chromosomal deletion disrupts Frizzled gene (FZD9)
• Multisystem disorder:
  1. Supravalvular aortic stenosis (SVAS)
  2. Mental retardation
  3. Distinct facial feature

Question 96

Dysregulated WNT Signaling & Diseases

What causes Osteoporosis-pseudoglioma syndrome? What are the symptoms?

Answer 96

• LRP5 mutations
• Severe thinning of the bones (Osteoporosis)
• Scoliosis
• Eye abnormalities
• Pseudogliomas in the retina

Question 97

Dysregulated WNT Signaling & Diseases

What mutations cause Medulloblastomia (cancer) in kids?

Answer 97

Mutations in β-catenin, or APC or AXIN genes

Question 98

Dysregulated WNT Signaling & Diseases

What mutation causes Colorectal Cancer?

Answer 98

Germline APC mutation

Question 99

Dysregulated WNT Signaling & Diseases

What mutations causes Turcot syndrome? What is the clinical outcome?

Answer 99

APC mutation→ Adenomatous polyps & primary brain tumors

Question 100

What are the two types of Protein Kinases? What is the Notch-Delta Pathway?

Answer 100

• Protein Kinases

1. Receptor Tyrosine Kinases
2. Hippo Signaling Pathway

• Notch-Delta Pathway: Juxtacrine signaling by ligand-receptor on adjacent cells

Question 101

Protein Kinases & Cell Signaling

What occurs in the Receptor Tyrosine Kinase (RTKs) pathway? What can a mutation of RTKs cause?

Answer 101

1. Receptor Tyrosine Kinases (RTKs) bind to ligands, dimerize and transphosphorylate
2. Kinase Domains in the “tails” of the RTKs transphosphorylate & activate RTKs.

• An inactivating mutations RTKs cause many diseases

Question 102

What is Milroy disease? What chromosome is affected? What symptoms are present?

Answer 102

• A mutation in the Kinase Domain (KD) of “Vascular endothelial growth factor receptor 3”,VEGF Receptor 3 (VGEFR3 or FMS-related tyrosine kinase 4 [FLT4]) results in the autosomal dominant lymphatic disorder
• Chromosome: 5q35 arm (FLT4 gene)
• Symptoms: Primary Congential Bilateral lymphedema, Fluid in the scrotum (hydrocele)

Question 103

How does the Notch-Delta Signaling Pathway (Juxtacrine Signaling) work?

Answer 103

• Delta/Jagged (from differentiated cell) mediated NOTCH signaling in progenitor cells, leads to γ-secretase mediate cleavage of the NOTCH intracellular domain (NICD)
• NICD moves to the nucleus and activates target gene that cause controlled differentiation or maintains stemness. In adjacent cells, NOTCH signaling is not active.

Question 104

Lateral inhibition of notch-delta signaling pathway maintains what?

Answer 104

Lateral inhibition maintains fixed number of cells in a differentiated state→proper organ formation & maintenance

Question 105

What diseases can arise from Abnormal Notch-Delta Signal Pathway (Juxtracrine Signaling)? What mutations arise and what are the clinical mainfestations?

Answer 105

1. Alagille syndrome

• JAGGED 1 or NOTCH2 mutations
• Malformed liver, kidney, heart, eyes & bones

2. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

• Due to due to NOTCH3 mutations
• Most common form of hereditary stroke disorder