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BMSC week 2: development and cytogenetics


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What is the most common cause of triploidy?
Fertilization of an ovum by two sperm.
What is the most common cause of tetraploidy?
Failure of cytokinesis in cell division post-fertilization.
What is mosaicism? How does it occur?
Mosaicism is the presence of two or more karyotypes in a single human. It is caused by abnormal events after fertilization, for example mitotic nondisjunction.
What is the most common identifiable cause of mental retardation?
Down syndrome
What are the risk factors for having a child with Down syndrome?
-maternal age > 35
-having already had a child with Down syndrome (recurrence risk = 1%)
What is the phenotype of Down syndrome patients?
-IQ = 30-60 (moderate retardation)
-congenital cardiac defects
-increased susceptibility to respiratory infections
-high incidence of early Alzheimer's disease
What type of chromosomes are involved in Robertsonian translocations? What DNA is missing in balanced carriers?
Acrocentric chromosomes are involved. The missing DNA would code for rRNA, but it is dispensable because there are 10 blocks of rRNA genes.
What is the phenotype of patients with Cri du chat syndrome? What is abnormal about the karyotype?
-severe mental retardation
-cat-like cry in neonatal period
Caused by deletion of part of 5p.
What is the genotypic difference between Prader-Willi syndrome and Angelman syndrome?
-Many patients with PWS have a deletion of paternally derived 15q11-13.
-Many patients with AS have a deletion of maternally derived 15q11-13.
What is a Barr body?
The inactivated X-chromosome in females; male cells do not have Barr bodies.
What is the mechanism of X-inactivation?
Transcription of the XIST gene (located in Xq13) produces an RNA which associates with the X-chromosome from which it was transcribed. This inactivates most of the chromosome.
What is Turner syndrome (genotypic and phenotypic)?
Genotype: one missing or defective X chromosome
-female, no ovaries
-failure of onset of menstruation
-minimal breast development
-pubic hair sparse or missing
-short stature/malformations (Xp deletion, iXq)
What is the phenotype of trisomy X patients?
-usually tall
-may have learning disabilities/behavioral problems
Under what circumstance can an XY patient be female? What is the phenotype?
SRY on Y chromosome is missing. The phenotype is similar to Turner syndrome.
What genotypes lead to Klinefelter syndrome? What is the phenotype?
-male, relatively small genitalia, infertile
-tall stature, long limbs
-breast development may occur
What is the phenotype of XYY patients?
-male, fertile
-mean intelligence decreased
-behavior problems
Under what circumstance would an XX patient be male? What is the phenotype?
SRY is translocated onto one of the X chromosomes. Males with this genotype are infertile.
How can flow cytometry be used to measure mitotic activity in a cell population?
Cells are stained with propidium iodide, which stains DNA. The amount of DNA per nucleus is measured. Cells in G2 and M have twice as much DNA as cells in G1.
What is the purpose of the ORC? When is it assembled?
The ORC marks where synthesis will occur; many initiation factors bind to it during G1. It is preassembled at the end of S phase in preparation for the next cycle.
What does cyclin A-CDK2 do? When does it appear in nuclei?
Cyclin A-CDK2 orchestrates a series of phosphorylations which trigger origin of replication firing. It appears in the beginning of S phase.
How is the cyclinB-CDK1 complex activated?
-Wee1 phosphorylates Tyr15
-CDK activating kinase (CAK) phosphorylates Thr161
-Cdc25 dephosphorylates Tyr15
What does cyclinB-CDK1 do?
-blocks initiation factors from binding to ORC
-helps activate anaphase promoting complex (APC), which activates separase
-triggers the cell to go from G2 to M phase
net result: blocks S, triggers M
What ensures that progression from M to G1 is irreversible?
-anaphase promoting complex (APC) degrades cyclin B in late anaphase
-cyclin D-CDK4/6 degrades APC in early G1
What is p16INK4a? What happens if this protein is deleted?
Inhibits cyclinD1-CDK4/6 complexes. If p16 is deleted, tumors/cancer occurs.
What is p21cip1?
-inhibits all cyclin-CDK complexes
-mediates p53-directed cell cycle arrest
What is p27kip1?
-inhibits all cyclin-CDK complexes
-plays role in arresting cells in G1
What happens if you add PDGF, EGF, or IGF-1 to G0-arrested fibroblasts?
Cell cycle is stimulated:
-G1 takes 8-12 hours
-S is finished by 24-36 hours
What does c-Fos do? What activates its transcription?
promotes progression from G1 to S (early response).
-growth factor binds/activates receptor tyrosine kinase
-ERK is activated, phosphorylates Elk1
-SRF-Elk1 is bound to SRE, c-Fos is transcribed
What does cyclin D-CDK4/6 do?
promotes progression from G1 to S (late response).
-mitogen sensor
-phosphorylates C-terminus of Rb
What does Rb do? What regulates it?
Represses E2F, a transcriptional activator, by binding it.
-phosphorylation by cyclin D-CDK4/6 or cyclin E-CDK2 inactivates it
What does E2F do? What regulates it?
Activates transcription of:
-cyclin E
-cyclin A
What does cyclin E-CDK2 do? What regulates it?
Phosphorylates Rb, inactivating it (therefore activating E2F).
-E2F positively regulates cyclin E transcription.
How does DNA damage arrest cell cycle?
-activation of p53 → transcription of p21CIP1 → inhibition of cyclin-CDK → arrest in G1 or S
-inactivation of Cdc25 → failure to activate cyclin B-CDK → arrest in G2
What is a circumstance which could arrest the cell cycle in M?
Chromosome unattached to spindle blocks anaphase promoting complex (APC) action → no separase is activated → no M
What are the two classes of qualitative (also known as discrete or categorical) variables?
-nominal (sorting, naming)
-ordinal (ranking)
What are the two classes of quantitative variables?
What is the difference between prevalence rate and incidence rate?
Prevalence: cases/population
Incidence: new cases/population/time
What is the relationship between incidence, prevalence, recovery, and death?
Prevalence = Incidence - Recovery - Death
What is kurtosis?
-When a graph does not have a normal distribution: too short, tall, skinny, or fat.
-When 68% of data does not lie within one std. dev. of the mean.
How is Relative Risk calculated?
incidence of disease in exposed group / incidence of disease in unexposed group
What does PTEN do?
It is a phosphatase that converts PIP3 to PIP2 (limits timing of growth factor signals).
What does PIP3 do? What regulates it?
Growth factor receptors activate PIP3 kinase, PTEN dephosphorylates it.
What are caspases?
Enzymes that contribute to apoptosis by cleaving critical proteins. Caspases preferentially cleave Asp-X-X-Asp or Glu-X-Asp sequences.
What are the two types of caspases, and which specific caspases are under each type?
Initiator: caspases 8, 9
Executioner: caspases 3, 7
What is FADD?
Fas-associated death domain. A cytosolic protein that interacts with Fas triplet clusters and procaspase-8.
What proteins must be included in a DISC (death inducing signaling complex) for it to induce apoptosis?
-at least 9 Fas molecules
-Fas-associated death domains
-procaspase-8 molecules (several)
Which members of the Bcl-2 family prevent apoptosis? Which induce cell death?
Prevent cell death:
Induce cell death:
How does cytochrome c contribute to apoptosis?
-Members of Bcl-2 family cause release of cytochrome c from mitochondria.
-Cytochrome c binds to Apaf-1 and it heptamerizes to form a spoked wheel, and recruits procaspase-9.
How do inhibitors of apoptosis proteins function? How are they regulated?
-block caspase action through active site
-mark for degradation through ubiquitin (XIAC only)
IAPs are inhibited by release of SMAC from mitochondria (caused by Bad, Bax, Bid).
Which embryonic development events occur in the first week?
-fertilization (usually fallopian tube)
-blastocyst formation
-implantation of trophoblast
What is the trophoblast? What is the embryoblast?
The trophoblast is the outer cell mass of the blastocyst. The embryoblast is the inner.
What is an ectopic pregnancy? What are risk factors and symptoms?
Implantation in a place other than the uterus. Risk factors are pelvic inflammatory disease and infertility problems. Symptoms are intense pelvic pain and vaginal bleeding.
What causes placenta previa?
Implantation in the lower part of the uterus, towards the cervix; this causes the placenta to obstruct the cervix.
What is a lithopedeon?
An asymptomatic ectopic fetus can die and calcify, becoming a "stone baby".
Where are the totipotent embryonic stem cells found?
What embryonic development events occurs in the second week?
-trophoblast differentiates into cytotrophoblast and syncytiocyte
-embryoblast subdivides into a bilaminar disc, which contains the hypoblast and epiblast
What is the syncytioblast? From what structure does it develop?
Invades into the endometrium to form the exchange network that is the primitive uteroplacental circulation. It develops from the trophoblast.
What is the cytotrophoblast? From what structure does it develop?
Expands mitotically into the syncytiotrophoblast to form primary chorionic villi. It develops from the trophoblast.
What is the epiblast? From what structure does it develop?
Epiblast cells cavitate to form the amnion, and eventually the entire adult body. They develop from the embryoblast.
What is the hypoblast? From what structure does it develop?
Hypoblast cells migrate along the inner surface of the cytotrophoblast and will form the primary yolk sac. They develop from the embryoblast.
What hormone do pregnancy tests check for? What structure produces this hormone and when?
human chorionic gonadotropin (hCG), by blood or urine. The syncytiotrophoblast produces it as early as 10 days post-fertilization.
What is a hydatidiform mole, or molar pregnancy?
A hyperplastic proliferation of the trophoblast cells within the uterine wall.
What is a choriocarcinoma?
A malignant tumor of trophoblast cells that can follow a normal pregnancy, abortion, or molar pregnancy.
What embryonic development events occur in the third week?
-gastrulation of the epiblast to form a trilaminar disc: epiderm, mesoderm, endoderm
-development of the primitive streak, primitive node, and notochord
What is the primitive streak?
A linear band of thickened epiblast which appears at the caudal end of the embryo (cloacal membrane) and grows cranially.
What is the primitive node?
A cluster of epiblast cells at the cranial end of the primitive streak, from which mesenchymal cells migrate to form the notochord.
How do organizing centers regulate gastrulation?
They are groups of cells which are capable of inducing differentiation in their neighbors by secreting diffusible growth factor signals.
What can cause conjoined (Siamese) twins?
Having two organizing centers in the embryo
What is caudal dysgenesis?
Gastrulation is interrupted, and the absence of sufficient mesoderm results in abnormal caudal structures.
What are sacrococcygeal teratomas?
Remnants of the primitive streak (which are pluripotent) proliferate into a tumor.
What is situs inversus (totalis)?
A type of laterality sequence (abnormal sidedness) caused by improper left-right signaling during gastrulation.
What embryonic development events occur in weeks 4-8?
-evolution of the body plan
-organogenesis from ectoderm, mesoderm, endoderm
What are some tissues/organs that develop from the endoderm?
-GI tract epithelium
What are some tissues/organs that develop from the mesoderm?
-axial skeleton
What are some tissues/organs that develop from the ectoderm?
-nervous system
How does the notochord form? What does it do?
The notochord forms from mesenchymal cells which migrate cranially from the primitive node. It induces the overlying ectoderm to become neuroectoderm.
How does the neural tube develop from the neural plate?
The neural plate folds in on itself to form the neural groove, which first fuses in the middle and then closes up both cranially and caudally to form the neural tube.
What are neural crest cells?
Pluripotent cells from the neural folds which migrate to various sites in the embryo.
How does the anterior portion of the neural tube develop during the fourth week?
First, three primary brain vesicles are formed. Later, these give rise to five secondary vesicles, which give rise to the brain structures.
What happens if the anterior neuropore fails to close?
anencephaly - absence of brain development
What happens if the caudal neuropore fails to close?
spina bifida - with occulta, meningocele (meninges and CSF outside the vertabrae), or myelomeningocele (meninges, CSF, and spinal cord outside the vertebrae)
What is one cause of piebald pigmentation?
Mutation of the c-kit receptor which leads to improper neural crest cell migration.
What are somites?
Undifferentiated blocks of mesodermal cells which disaggregate into sclerotome (vertebrae), myotome (muscle), and dermatome (skin)
How is innervation organized for dermatomes and myotomes?
Dermatomes and myotomes are innervated by their segments of origin.
How is herpes zoster related to shingles?
When herpes zoster reactivates in a spinal ganglion, it causes shingles in the dermatome that the ganglion innervates.
What is upper brachial plexus injury?
Excessive separation of the neck and shoulder stretches or tears the C5 and C6 nerves, leading to numbness/paralysis in the upper limb.
What is the vitelline duct? What occurs if the vitelline duct persists?
The vitelline duct connects the midgut with the yolk sac. Persistence of the duct leads to:
-Meckel's diverticulum
-omphalomesenteric fistula
-omphalomesenteric cyst
-omphalomesenteric ligament
What is an omphalocele?
The midgut retracts into the abdominal cavity from the umbilical cord by week 10 (rotating 270° around superior mesenteric artery). Failure to retract leads to omphalocele.
How is an annular pancreas formed?
The pancreas develops from the dorsal and ventral pancreatic buds, which fuse as the gut rotates. Inappropriate rotation and fusion leads to annular pancreas.
How is stenosis or atresia of the intestinal lumen caused? How is it diagnosed?
-failure of recanalization
It is diagnosed by the "double bubble" on x-ray (bubble of gas in the stomach, and one in the duodenum), and bile in vomit (greenish) from ampulla of Vater.
What is the proctodeum? What happens if it does not degenerate?
Endoderm and ectoderm are in direct contact at the proctodeum. Failure to degenerate leads to imperforate anus.
Which congenital malformation is seen in 2% of people, 2 ft. from the ileocecal valve, 2 in. long, has peak incidence of age 2, has 2:1 male predominance, and contains gastric mucosa in 1 out of 2 patients?
Meckel's diverticulum
What is a homeotic mutation?
Changes in one body part to another (for example, extra ribs in humans, or antennapedia in flies)
What do homeobox genes code for?
Transcription factors that contain a helix-loop-helix binding domain and bind to the major groove of DNA. They activate genes which regulate segmentation and axis formation.
How does the order of Hox genes determine the body axis?
The genes at the 3' end are expressed first and are correlated with anterior structures.
How does endogenous retinoic acid affect transcription of Hox genes?
Retinoic acid binds the retinoic acid receptor, which binds the RARE before paralogue 1. The closer the gene is to the enhancer, the more sensitive it is to retinoic acid.
How does exogenous retinoic acid affect transcription of Hox genes?
Exogenous RA rostralizes development, and may cause cleft palate, micrognathia, and other birth defects.
What is the difference between the arrangement of Hox genes in Drosophila and humans?
Drosophila has one cluster of Hox genes, humans have four (A-D, 13 paralogues total)
What is the length of a full term human pregnancy?
38 weeks after conception, or 40 weeks after last normal menstrual period
What is fundal height? Why is it measured?
The height of the uterus in cm from the top of the uterus to the pelvic bone; it correlates to the number of weeks since conception.
What are some developmental events that occur in the fetus between 9-12 weeks?
-length more than doubles
-intestinal coils extend into umbilical cord until week 10, return to abdominal cavity by week 11
-ossification centers appear in cranium and long bones by week 12
What are some developmental events that occur in the fetus between 13-16 weeks?
-rapid growth of limbs and body
-limb movements begin
-external genitalia differentiated by week 14
-bones visible on ultrasound by week 16
What are some developmental events that occur in the fetus between 17-20 weeks?
-fetal movements can be felt by mother
-limbs reach final relative proportions
-brown fat forms
-skin covered with vernix caseosa
-hair, eyebrows, lanugo hair visible at 20 weeks
-females: uterus formed, canalization of vagina, formation of primordial ovarian follicles begins
-males: testes begin to descend but still in abdomen
What fetal developments occur between 21-25 weeks?
-rapid eye movements begin
-surfactant secretion in the alveoli at 24 weeks
What causes respiratory distress syndrome? How can it be treated?
-babies born without surfactant (premature)
-babies born to mothers with diabetes
Steroids (beta methazone) can be given to help mature the lung.
What fetal developments occur between 26-29 weeks?
-enough surfactant to allow lungs to expand
-CNS supports rhythmic breathing, body temperature regulation
-eyelids open at 26 weeks, hair developed
-nails present, subcutaneous fat accumulation
-fetal spleen initially a site of hematopoiesis, bone marrow takes over by 28 weeks
What fetal developments occur between 30-34 weeks?
-preterm babies this age can usually survive
-difficult to suck, swallow, and breathe at same time
-skin is smooth, limbs have chubby appearance
What fetal developments occur between 35-38 weeks?
-nervous system can carry out some integrative functions
-testes in scrotum
-white fat is 16% of body weight
-weight gain is 14 g/day
What factors amplify fetal growth?
-glucose availability
-amino acids
What factors retard fetal growth?
-smoking (low oxygen)
-drugs, alcohol
-multiple pregnancy
-impaired blood flow (hypertension)
What is AFP? What is the time window for AFP testing?
Alpha feto protein, which is produced by the fetal liver and is present in the mother's blood. It is usually tested between 15-18 weeks, along with hCG and unconjugated estriol.
What does CVS test for? When is the test usually performed?
Chorionic villus sampling is performed to check the karyotype. It is performed between 10-12 weeks.
What does amniocentesis test for? When is the test usually performed?
Amniocentesis is performed to check the karyotype. It is performed at 15-21 weeks, and is safer than CVS.
Which nuclear receptors are cytosolic? Which are in the nucleus?
-cortisol receptor
-estrogen receptor
-progesterone receptor
-vitamin D receptor
-thyroid hormone receptor (bound to DNA)
-retinoic acid receptor (bound to DNA)
What effects do hormone binding have on nuclear receptors?
-conformational change
-dissociation of inhibitory factors
-unveils DNA binding domain
-nuclear translocation of cytosolic receptors
How are G-proteins attached to the membrane?
The α and γ subunits are attached by farnesylation.
What happens when a ligand binds a G-protein coupled receptor?
-activated receptor catalyzes exchange of GDP for GTP on α subunit of G-protein
-the α subunit dissociates from βγ subunits and activates the effector protein, hydrolyzing GTP
What is a GAP?
GTPase accelerating protein; it hydrolyzes the GTP on the α subunit
What does cAMP do? What regulates it?
cAMP activates Protein Kinase A (PKA). It is synthesized by adenylate cyclase (from ATP). It is destroyed by phosphodiesterase (to AMP).
What does adenylate cyclase do? What regulates it?
Adenylate cyclase synthesizes cAMP. It is activated by Gαs, and inactivated by Gαi.
How does low blood glucose promote glycogen breakdown?
-low glucose stimulates glucagon release
-glucagon binds to Gαs receptor and stimulates PKA
-PKA phosphorylates and activates phosphorylase kinase
-phosphorylase kinase promotes glycogen breakdown
How does PKA influence transcription?
-PKA phosphorylates inactive CREB
-CREB-binding protein (CBP) binds to activated CREB
-they bind to CREB-binding element on DNA and activate transcription
How does cholera toxin affect cAMP levels?
ADP-ribosylates Gαs, locking it "on", leading to upregulation of adenylate cyclase, increasing cAMP.
How does pertussis toxin affect cAMP levels?
ADP ribosylates Gαi, inactivating it. This allows adenylate cyclase to act and increase cAMP.
What do beta-blockers do?
-block β2-adrenergic signaling
-treats hypertension, anxiety
What does Gαq do?
Activates phospholipase C (PLC)
What does phospholipase C (PLC) do?
Hydrolyzes PIP2 into IP3 and DAG
What does IP3 do?
Opens a Ca2+ channel in the ER membrane
What happens to diacylglycerol after PLC cleaves PIP2?
-remains in membrane and be converted to arachidonic acid
-can activate certain isoforms of Protein Kinase C
What does PKC do?
-desensitization of signaling pathways
-gene transcription
What are some cytosolic targets of Ca2+?
-some Protein Kinase C isoforms
-enzymes involved in cell division
What is calmodulin?
Related to troponin C. When bound to Ca2+, can activate:
-CaM kinases
-membrane transport proteins
-metabolic enzymes
How are CaM kinases regulated?
-Ser/Thr kinases
-partially activated by phosphorylation
-fully activated by Ca2+/calmodulin
-"super" activated by autophosphorylation
-deactivated by dephosphorylation
What are two examples of CaM kinases?
-myosin light chain kinase: phosphorylates the light chain of myosin → smooth muscle cell contraction, non-muscle cell motility
What are the 2 steps in receptor tyrosine kinase activation?
-increase in intrinsic catalytic activity (receptor dimerization and cross-phosphorylation)
-creation of binding sites to recruit downstream components
How do interferons initiate signaling? What is this pathway called?
Jak-STAT pathway
-interferon receptors associate with tyrosine kinases
-when interferon binds, the receptor dimerizes and Jaks cross-phosphorylate each other
-activated Jaks phosphorylate Tyr residues on the receptors
What are STATs? What do they do?
-activated interferon receptors recruit STATs, then phosphorylate them
-STATs translocate to the nucleus and activate transcription of genes involved in immune and inflammatory response
What type of receptor does TGF-β have? What happens when TGF-β binds it?
-receptor Ser/Thr kinase
-binding of TGF-β causes the receptor to recruit and phosphorylate a type 1 receptor
What are Smads? What do they do?
-they are recruited and phosphorylated by type 1 receptors
-they translocate to the nucleus, bind to a TGF-β response element, and activate transcription
What are the 3 types of accessory proteins that modulate cycling of G-proteins between GTP/GDP?
-regulators of G-protein signaling (GTPase activating proteins: GAPs)
-guanine nucleotide exchange factors (GEFs)
-guanine nucleotide dissociation inhibitors (GDIs)
What are the 3 members of the MAPK family? What does MAPK stand for and what is another name for it?
-Erk 1/2
-p38 MAPK
MAPK stands for mitogen activated protein kinase; it is also called extracellular signal regulated kinase (ERK)
How do MAPKs work? What do they do?
-Ser/Thr kinases
-activated by phosphorylation on a Thr and Tyr (TXY) in the activation loop
-play a role in proliferation
What do MAPKKs do?
phosphorylate a Thr and Tyr (TXY) on MAPKs
What is Raf?
A MAPKKK which is activated by Ras. It phosphorylates MEK 1/2, activating it.
What is MEK 1/2?
A MAPKK which is activated by Raf. It phosphorylates ERK 1/2 on Thr and Tyr in its activation loop.
What is ERK 1/2?
A MAPK which influences transcription of genes that control cytoskeleton, motility, cell cycle, and proliferation.
What is p38 MAPK?
A MAPK which influences transcription of cytoskeleton and apoptosis genes.
What is SAPK/Jnk?
A MAPK which controls expression of the gene c-jun.
What is Src? What does it do?
A non-receptor tyrosine kinase (and oncogene); it can:
-phosphorylate EFGR (a mitogenic growth factor)
-link some GPCRs, non-receptor tyrosine kinases, extracellular matrix to MAPK
-phosphorylate proteins involved in focal contacts so cell rounds up
What is PI3 kinase? What is it for?
It phosphorylates the 3 carbon on phosphatidylinositol and its derivatives. It is involved in cell growth, migration, and glucose uptake.
How is PI3 kinase activated and inactivated?
-receptor tyrosine kinases (binding to phosphotyrosine)
-G-protein coupled receptors
-inositol phospholipid phosphatases (PTEN)
How does the insulin receptor influence cell proliferation?
When activated, the insulin receptor interacts with Shc, initiating the Ras-MAPK pathway, leading to cell proliferation.
How does the insulin receptor influence glucose uptake, glycogen synthesis, and protein synthesis, and lipid metabolism?
When activated, the insulin receptor interacts with IRS proteins, which stimulate PI3-kinase. This leads to an increase in PIP3.
What are possible causes of insulin resistance? What is the effect?
-inhibition of insulin receptor tyrosine kinase activity (for example by PC-1, a membrane glycoprotein)
-Ser phosphorylation of IRS-1 by MAPK, mTOR, can reduce insulin stimulated tyrosine phosphorylation
-type II diabetes
How can a signal be downregulated?
-receptor sequestration
-receptor downregulation
-receptor inactivation
-inactivation of signaling protein
-production of inhibitory protein
What are some structural features of Src?
-myristoylated N terminus
-SH3 domain (binds polyprolines)
-SH2 domain (binds phosphotyrosines)
-tyrosine kinase domain

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