Unit 3.L2-Developmental Signaling & Molecular Basis of Birth Defects Flashcards
(105 cards)
1
Q
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?
A
- 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
2
Q
What factors can cause birth defects and include the percentages?
A
- 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%:
3
Q
What normally occurs during the first 2 weeks of development? What birth defects can occur?
A
- Normally, the period of dividing zygote, implantation, and bilaminar embryo
- Birth Defects: Embryonic death & spontaneous abortion
4
Q
What period is the most suspectible period to birth defects? What are the major birth defects that can occur during the this time?
A
3-8 Weeks (Main Embryonic Period): Most Susceptible Period
- Major (congential) birth defects:
- Amelia/limb defects
- Cardiac defects (TA, ASD,VSD) (Heart)
- Neural tube defects
- Spina bifida cystica
- Eye defects (Microphthalmia, cataracts, glucoma)
- Mental retardation
- Amelia/Meromelia (Upper&Lower limbs)
- Cleft lip (Upper lip)
- Low-set malformed ears & deafness
- Enamel hypoplasia and staining
- Cleft Palate
- Masculinazation of female genitalia
5
Q
What birth defects occurs in the Fetal Period (9-38 wks)?
A
9-38 Wk Less Sensitive to Teratogens
- Minor Functional defects
- Palate, teeth, genitalia anomalies
6
Q
When is the development of the embryo most easily disrupted?
A
Development of the embryo is most easily disrupted during tissues & organs formation
7
Q
What is the critical period for brain development? What happens in this period?
A
Critical period for brain development is long (3-16 weeks) and starts early; thus, maximum defects are observed in the brain
8
Q
When does the heart develop? What occurs during this period?
A
Heart develops in the 3-8 weeks / organogenetic period; major defects occur in this period.
9
Q
When do pregnant ladies must remain the most careful?
A
Pregnant lady must remain most careful: first 3-16 weeks (mental retardation can occur till 16 weeks)
10
Q
For the organ listed below what are the number of incidence of birth defects that could occur:
- Brain
- Heart
- Kidneys
- Limbs
- All other
- Total
A
- 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
11
Q
What does the birth defect types that arise depend on?
A
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)
12
Q
What are common teratogens that cause birth defects and what defects do they cause?
A
- High levels of ionizing radiation:
- CNS defects (brain & spinal cord)
- Eye defects
- Rubella virus infection:
- Eye defects (glaucoma & cataracts)
- Deafness
- Cardiac defects
- Thalidomideinduces defects:
- Limb/digits
- Cardiac
- Kidney
Risk of Birth Defects Increases during the Early Organogenetic Period
13
Q
How much birth defects are caused by mutant genes?
A
Mutant genes cause apporximately one-third of all birth defects
- Sex-chromosomes
- Autosomal
14
Q
What causes chromosomal aberrations (non-disjunction)?
A
Malfunctioning in mitosis or meiosis causes chromosomal aberrations
15
Q
Aberrant Chromosome Numbers at Birth
What is Aneuploidy? How common is it? Include example.
A
- 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)
16
Q
What is Polyploidy? Include example. How can it be caused?
A
- 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
17
Q
What is Hypodiploidy? Include examples.
A
- Decrease in One or more chromosome from 46.
- Example: 45, as in X0 (Turner syndrome; 1% survive)
18
Q
What is Hyperploidy? Include examples.
A
- More than 46 chromosomes
- Example: 47 or more, as in trisomy 21 or Down Syndrome
19
Q
What is Monosomy? What is the normal life expectancy? Include examples.
A
- 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
20
Q
What leads to nondisjuction during maternal or paternal gametogenesis?
A
A failure of a chromosomal pair or two chromatids of a chromosome to disjoin at meiosis leads to “nondisjunction during maternal or paternal gametogenesis.
21
Q
What is the result of nondisjuction during maternal or paternal gametogenesis?
A
Extra chromosomal pair or chromatids in one daughter cell & missing chromosome in other daughter cell
22
Q
What is Trisomy 21 (Down Syndrome)? What is the number of incidence? Down syndrome represents how many institutionalized individauls w/ severe mental retardation?
A
- 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.
23
Q
What is the life expectancy of people w/ Down Syndrome? What are physical apperances present?
A
- 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
24
Q
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?
A
- 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
25
What is Mosaicism?
**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.
26
List the Incidence of Down Syndrome at the maternal ages below:
* 20-24
* 25-29
* 30-34
* 35
* 37
* 39
* 41
* 43
* 45+
* 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
27
What are physical signs of Down Syndrome? (13)
* 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**
28
What is Edwards Syndrome (Trisomy 18)? How common in US births? What are side effects present?
**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)**
29
What is a major side effect of trisomy 18 (Edwards Syndrome) ?
**Micrognathia (undersized lower-jaw)**
30
What is Patau Syndrome (Trisomy 13)? How common in US births? What are the side effects present?
**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**)
31
What is the cause of Trisomy 13 (Patau Syndrome)? What has reduced incidence?
* Cause: **Idiopathic; increases with mother’s age**
* **Prenatal examination**, **elective abortions** & loss of a child through **miscarriages** have reduced incidence.
32
What is Reciprocal translocation? What does it cause?
If two nonhomologous chromosomes exchange pieces, it is called a reciprocal translocation. Translocation **does not necessarily** cause abnormal development
| Structural chromosomal abnormality
33
What are Balanced translocation carriers? What is the caveat concerning balanced translocation?
* Persons with reciprocal translocation but **no phenotype**
* **Caveat**: But their **gametes** have **abnormally translocated** chromosomal regions which may show up in the progeny
34
How many infants with down syndrome have translocation trisomies?
**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**
35
What is Chromosomal Deletions?
When a **chromosome breaks**, part of it may be **lost; called deletion**
36
What is the chromosomal deletion that causes Cri du chat syndrome? What are the diagnosis present?
## Footnote
Autosomal Deletions
* **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)
## Footnote
Karyotype of the child shows a terminal deletion (5p) of the short arm p of. chromosone 5
37
What is the chromosomal deletion that causes Turner Syndrome? What are the clinical presentations?
* 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
38
What are common trisomy of Sex Chromosomes? What sex do they affect? Number of incidence? Usual characteristics?
**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**
39
How often are gene mutants seen in birth defects? What occurs d/t gene mutations?
* 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
40
What causes the Autosomal Dominant birth defect **Achondroplasia**? What clinical features are present?
* **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
41
What is needed for phenotype of Autosomal Recessive Inheritance? List examples
* 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
42
What causes the Autosomal Recessive birth defect **Congenital Suprarenal (Adrenal) Hyperplasia**? What clinical features are present?
* **Excessive androgens** due to congenital **adrenal hyperplasia**
* Clinical features: Causes masculinized external genitalia (enlarged clitoris & fused labia majora)
43
# Sex-chromosome Aberration
What is Fragile X Syndrome? What disorders is it associated with? What defect causes this syndrome?
* 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 the **FMR1** (Fragile X Mental Retardation 1) gene required for **cognitive development**
.
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?
* 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**
## Footnote
Need up to 55 CGG to have Fragile X Syndrome
45
How does Fragile X Syndrome affect male and females? What clinical features occur?
* **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**
46
How is embryogenesis regulated? What can lead to birth defects during embryogenesis?
* Embryogenesis is regulated by multiple cell-signaling cascades
* Aberrant cell-signaling leads to birth defects
47
What are the three modules of Cell signaling Pathway?
1. **Reception** (Receptors)
2. **Transduction** (signal-transduction pathway)
3. **Response** (Activation of cellular responses)
48
What are the needs and consequences of Cell Signaling in Development? (7)
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
49
What is the language of signaling? List the examples
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
50
What are the major types of signals for the cells?
* Local signals (**Autocrine/Paracrine**)
* Hormonal signals (**Hormones/Endocrine**)
51
For Local signals (Autocrine/Paracrine):
* What is the distance?
* What is it dependent on?
* What cells are affected?
* Example
* Short-distance
* Contact dependent (autocrine)
* Affect the cells that produce them (autocrine)
* Affect nearby cells (diffuse) (paracrine)
* Synaptic
## Footnote
Autocrine (same cell)
Paracrine (adjacent cells-5,10,20 cells down)
52
For Hormonal signals (Hormones/Endocrine):
* What is the distance?
* What cells are affected?
* What is used for distribution?
* Long-distance
* Multicellular organisms
* Use circulatory system for distribution
53
What are the four major ways of cellular signaling during Embryogenesis?
1. Contact-dependent (Juxtacrine)
2. Paracrine
3. Synaptic (Paracrine)
4. Endocrine
54
Where do Autocrine and Paracrine signaling bind to?
* **Autocrine signals** bind to receptors on the **same cell** that secret them
* **Paracrine signals** bind to receptors on **nearby cells**
## Footnote
NOTE: cells without receptors for a particular signal do not respond to that signal
55
What are the main Endocrine signals in early development? (3) How are circulating signals transported?
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
56
What is the Cell's signaling cascade during intracellular signaling? (5)
1. **Stimulus (Ligand as Signal)**
2. **Stimulus sensing (Receptors)**
3. **Communication (Adaptors)**
4. **Information processing (Transducers)**
5. **Decision making (Effectors)**
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?
* Receptors bind signaling molecules (**ligands**)
* Receptors are **highly sensitive and specific**
* Typical signal molecule **concentration <10^8 M**
* **>1500** human genes encode receptors
58
# Membrane & Intracellular Receptors
What are the 2 types of receptors and where are they located?
* **Cell surface-Most receptors** (hydrophilic-goes through blood)
* **Intracellular-Some receptors** (hydrophobic-requires carrier protein)
* Receptors: For light, gas or chemicals
59
What are the 2 types of Developmental Signaling and include examples?
1. Intercellular Communication
* Gap junctions
* Cell Adhesion Molecules
2. Morphogens
* Extrinsic Chemical Gradients for Cell-Signaling
60
# Intercellular Communication
What makes up each Gap Junction?
Two **hemichannels (connexons)**
61
# Intercellular Communication
What does each hexameric **connexon** consist of?
Consist of **6 connexin** subunits
## Footnote
6 connexin make 1 Hemichannel (Connexon)
62
# Intercellular Communication
Each Connexin (Cx) molecule comprises of?
* **4 transmembrane domains** + **2 Extracellular domains (N-terminus & C-terminus)**→Cytoplasmic/intracelluar
63
Humans have how many connexin-type molecules? What are the different gap junctions that can arise and why?
* 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
## Footnote
Note: -typic (different cell), -meric (same cell)
64
What are the Protein Elements of a Generic Connexin? (5)
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)
65
What is the function of Gap Junction Intercellular Communication (GJIC) in development?
**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
66
What is the function of Bound Connexons (Gap Junction) in the nervous and cardic systems?
GJIC establish electrical cell coupling (“electrical” synapse)
67
What are the connexins for the organs/tissues listed below:
* Heart, brain
* Heart, pancreas
* Myelin
* Pancreas, brain
* **Connexin Cx43 (heart, brain)**
* **Cx45 (heart, pancreas)**
* **Cx32 (myelin)**
* **Cx36 (pancreas, brain)**
68
What is the function of unbound connexons (hemichannels; connexin molecule)?
Exchange ions/small molecules between Cytoplasm←→ extracellular matrix
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?
* **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)
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?
* **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**)
71
# Intercellular Communication
What are Cell Adhesion Molecules (CAMs)? What is their function? What is the structure?
* 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
## Footnote
Other examples: NCAM (neural cell), PCAM (platelet), ICAM (immunoglobin)
72
# Intercellular Communication
What are two classes of Cell Adhesion Molecules (CAM) present in Embryo Development?
1. **Cadherins**
2. **Immunoglobulin superfamily of cell adhesion molecules (>700 members)**
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?
**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**
74
What is the function of E-cadherin? What does a loss of E-cadherin cause?
* Function: E-cadherin maintains epithelial phenotype.
* **Loss of E-cadherin cause EMT**, which is required for the **formation & movement of neural crest cells**
75
# Immunoglobulin superfamily of cell adhesion molecules
What is the structure of the **Neural cell-adhesion molecule (NCAM)**? What transmits the Intracellular signaling?
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**
76
What are the functions of Neural cell-adhesion molecule (NCAM)?
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**
77
What are Morphogens and include examples?
**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**
78
What proteins/factors are part of the TGF-β Superfamily?
* TGF-β
* BMPs
* Activin
* Nodals
79
What are the three TGF-β Ligand isoforms?
* TGF-β1
* TGF-β2
* TGF-β3
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?
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-SMADs**2/3**)**
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.
81
What is the developmental function of TGF-β?
TGF-β instruct **dorsoventral patterning, cell fate decisions, formation of specific organs, including the nervous system, kidneys, skeleton & hematopoiesis**
82
# Sonic Hedgehog Signaling (SHH)
What occurs in the Repressed SHH Pathway (SHH not present)?
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**
83
# Sonic Hedgehog Signaling (SHH)
What occurs in the Activated SHH Pathway?
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**
## Footnote
SHH Processing→N-Shh
* N-term: Palmitate
* C-term: Cholesterol
84
Sonic Hedgehog Pathway (SHH) defects cause what?
* 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**
85
What is Holoprosencephaly?
* 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.
86
What does SHH mutation cause?
* **Holoprosencephaly**, a congenital brain defect; **two fused cerebral hemispheres**
* **Anophthalmia or cyclopia**
87
What does Teratogen cyclopamine inhibits and what are its effect? What can the consumsion of Corn lily cause?
* Teratogen cyclopamine inhibits **Smoothened→activates GLI-R & abrogates SHH signaling**
* Consuming Corn lily→**Cyclopia**
## Footnote
Corn lily (Veratrum Californicum) or Vetch Weed
Alkaloid: Cyclopamine/11-deoxyjervine
88
What can an inborn error of cholesterol synthesis cause?
Inborn error of cholesterol synthesis→ **abrogates SHH signaling**→ **Smith-Lemli-Opitz syndrome** → **Holoprosencephaly**
89
What does GLI3 mutations cause?
GLI3 mutations→ **Autosomal dominant polydactyly syndromes (Greig cephalopolysyndactyly syndrome)**
90
The WNT/β-Catenin Pathway signaling is complex. What are the three signaling pathways?
1. **The classical/canonical β-catenin–dependent pathway**
2. Wnt/calcium pathway
3. Planar Cell Polarity (PCP) pathway
91
What occurs in the Inactive Classical WNT/β-catenin pathway?
**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**
## Footnote
Multiprotein complex: APC (Adenomatous polyposis coli), **GSK3** (Glycogen Synthase kinase 3) & Axin
92
What occurs in the Active Classical WNT/β-catenin pathway?
**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**
## Footnote
Multiprotein complex: APC (Adenomatous polyposis coli), GSK3 (Glycogen Synthase kinase 3) & Axin
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What is the multiprotein complex in the Classical Wnt/B-catenin pathway?
* APC (Adenomatous polyposis coli)
* GSK3 (Glycogen Synthase kinase 3)
* Axin
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What diseases/disorders can arise because of Dysregulated WNT Signaling?
Several Developmental Disorders:
1. Williams-Beuren syndrome
2. Osteoporosis-pseudoglioma syndrome
Tumors & cancers
3. Medulloblastoma in Kids
4. Colorectal Cancer
5. Turcot syndrome
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# Dysregulated WNT Signaling & Diseases
What causes Williams-Beuren syndrome?
What are the symptoms?
* Chromosomal deletion **disrupts Frizzled gene (FZD9)**
* Multisystem disorder:
1. Supravalvular aortic stenosis (SVAS)
2. Mental retardation
3. Distinct facial feature
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# Dysregulated WNT Signaling & Diseases
What causes Osteoporosis-pseudoglioma syndrome? What are the symptoms?
* **LRP5 mutations**
* Severe thinning of the bones (Osteoporosis)
* Scoliosis
* Eye abnormalities
* Pseudogliomas in the retina
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# Dysregulated WNT Signaling & Diseases
What mutations cause Medulloblastomia (cancer) in kids?
Mutations in **β-catenin, or APC or AXIN** genes
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# Dysregulated WNT Signaling & Diseases
What mutation causes Colorectal Cancer?
**Germline APC mutation**
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# Dysregulated WNT Signaling & Diseases
What mutations causes Turcot syndrome? What is the clinical outcome?
**APC mutation**→ Adenomatous polyps & primary brain tumors
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What are the two types of Protein Kinases? What is the Notch-Delta Pathway?
* Protein Kinases
1. Receptor Tyrosine Kinases
2. Hippo Signaling Pathway
* Notch-Delta Pathway: **Juxtacrine** signaling by **ligand-receptor** on adjacent cells
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# Protein Kinases & Cell Signaling
What occurs in the Receptor Tyrosine Kinase (RTKs) pathway? What can a mutation of RTKs cause?
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
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What is Milroy disease? What chromosome is affected? What symptoms are present?
* 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)
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How does the Notch-Delta Signaling Pathway (Juxtacrine Signaling) work?
* **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.
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Lateral inhibition of notch-delta signaling pathway maintains what?
Lateral inhibition **maintains fixed number of cells in a differentiated state**→**proper organ formation & maintenance**
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What diseases can arise from Abnormal Notch-Delta Signal Pathway (Juxtracrine Signaling)? What mutations arise and what are the clinical mainfestations?
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**
