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12/13/16 Corbo • Briefly describe the function and component parts of a transcription factor. What is a transcription factor? A transcription factor is a protein with two parts: (1) A sequence-specific DNA-binding domain (2) An activation or repression domain Activation domain Transcription factor DNA-binding domain DNA CTAATCCC • In a brief paragraph, describe how a neural progenitor population can give rise to different neuronal cell types at different time points during development. The competence model of retinal development Competence model: progenitors pass through a series of competence states, during each of which the progenitors are competent to produce a subset of retinal cell types. Environmental factors: (1) Small molecules (2) Secreted proteins (3) Cell surface molecules Progenitor Etc. Competence • Time Differentiated cell types • Is neuronal cell type production probabilistic or deterministic? Cellular differentiation on an epigenetic landscape Fertilized egg Differentiated cell types • Describe the location within the ventricular epithelium of a neural progenitor at the various stages of the cell cycle. What is this movement process called? The cell cycle in the developing retina Basal Apical Start near ventricle (apical) Nuclei move towards basal surface DNA replicates (s phase) Nuclei move back towards ventricle Reach ventricle and divide (m phase) Repeat Interkinetic nuclear migration Taghert • Papers Kim • Explain the distinction between the extrinsic and intrinsic pathway of apoptosis. • What are key differences in the morphology and mechanism of apoptosis and necrosis? • Apoptosis – Regulated: enzymatic steps, requires energy. – Requires transcription and protein synthesis – No loss of membrane integrity – Cytoplasm shrinks – Formation of apoptotic bodies on membrane (vesicles) – Cell kind of implodes/fragments into smaller pieces • Minimize damage to neighboring cells • Necrosis – Unregulated no energy requirement – Does not require transcription and protein synthesis – Loss of membrane integrity – Cytoplasm swells – No vesicle formation – Complete lysis of cell. • Can cause damage to neighboring cells • What is an explanation for the failure of caspase inhibitors to protect injured neurons in stroke or neurodegenerative diseases? • What is an explanation for the failure of caspase inhibitors to protect injured neurons in stroke or neurodegenerative diseases? – I think he said this last year: by the time the caspase inhibitors are applied, the cell has already committed to apoptotic death. Injury or stress has yielded an irreversible death decision, on which the inhibition of caspase has no effect. – Necrosis rather than apoptosis? • Co-receptor systems for neurotrophic factors are ubiquitous. Name two examples neurotrophic factors that use co-receptors (name ligand and the receptors). What might be a teleological reason for having a coreceptor system? Basically anything + p75 P75 + Trk: NGF or NT are ligands. P75 + NogoR/Lingo: Nogo is the ligand Why: Efficient Ensures death domain present Campenot Chamber Gabel • What chemical modifications are added to histones? What are the classes of enzymes that write and erase each of these histone modifications? Histone modifications: Writers and Erasers Histone acetyl transferases Histone deacetylases (HDAC) e.g. Creb binding protein CBP e.g. HDAC1-6 Histone methyltransferases e.g. MLL3 Histone demethylases e.g. LSD1 Cota et al. Pluirpotent Stem Cells 2013 • What chemical modifications are added to histones? What are the classes of enzymes that write and erase each of these histone modifications? – Epigenetic writers: • histone acetyltransferases (HATs) • histone methyltransferases (HMTs) • kinases – Epigenetic erasers: • histone deacetylases (HDACs) • lysine demethylases (KDMs) • phosphatases • Name two different consequences that histone modifications can have when present on a nucleosome. – Do the different chemical modifications on histones have the same effect regardless of which amino acid they are added to on the histone? – What histone modifications are associated with active or repressed gene-regulatory elements? • Name two different consequences that histone modifications can have when present on a nucleosome. – facilitate or repress transcription • Do the different chemical modifications on histones have the same effect regardless of which amino acid they are added to on the histone? – No. • H3K4me2/3 is associated with transcriptional activity. • Methylation of H3K9me2/3 is associated with repression • Name two different consequences that histone modifications can have when present on a nucleosome. – Do the different chemical modifications on histones have the same effect regardless of which amino acid they are added to on the histone? – What histone modifications are associated with active or repressed gene-regulatory elements? • What histone modifications are associated with active or repressed gene-regulatory elements? – Acetylation typically activates (HATs). – De-acetylation represses (HDACs) – Histone ubiquitination also represses • What proteins and DNA modifications are uniquely enriched in neuronal chromatin? Unique forms of DNA methylation are enriched in the neuronal genome Tahiliani et al. Science, 2009 5’ 3’ m CG GCm 3’ 5’ 5’ 3’ m CA GT Xie et al. Cell 2012 All cell types 3’ 5’ 5’ 3’ hm CG GCm Kriaucionis et al. Science, 2009 Enriched in neurons 3’ 5’ • What are two examples of disrupted epigenetic mechanisms that lead to neurodevelopmental disease? Cytosine methylation at CpGs is associated with gene repression 5’ 3’ m CG GCm 3’ 5’ Xie et al. Cell 2012 Aberrant DNA methylation underlies Fragile X-syndrome DNA methylation typically represses transcription - ~25% of males with the disorder have autism. - Prominent cause of syndromic autism, accounts for 1-2% of all autism. - Gene identified by Verkerk et al. Cell 1991 Robertson & Wolfe Nature reviews genetics 2000 Fragile X: methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product Mutations in the Methyl-cytosine binding protein2 (MeCP2) lead to Rett syndrome -Mapped to X chromosome and cloned using rare familial cases, confirmed by sequencing sporadic cases -Because of random X-inactivation Females with Rett are MECP2 -/+ and are a mosaic of MeCP2-expressing and MeCP2-null cells. Boys that are MECP2 -/y die just after birth with severe encephalopathy. -MeCP2 is expressed in all cells to some extent, but is highly enriched in neurons, building up postnatally. NCoR me Ac Ac me Ac me Ac Ac MeCP2 MeCP2 me Ac Ac Ac me MeCP2 me DNA methylation & genomic imprinting contribute to Angelman Syndrome -Angelman syndrome is characterized by little or no verbal communication, Intellectual disability, ataxia, seizures, happy demeanor. -It is caused by mutation of Ube3a. Because this gene is imprinted in the brain (expressed only from one allele), heterozygous disruption causes complete loss of ube3a. Wild type Expression of maternal Ube3a allele Ube3a m-/p+ No Ube3a expression Adapted from Li & Bartolomei Cell 2013 • What are three major criteria for judging the validity of a disease model? MeCP2 knockout mice: a model model Evaluating a disease model: Construct Validity How well does the underlying cause of dysfunction in the model replicate the human cause. Normal MeCP2 KO Face Validity How well does the model reflect disease phenotypes and pathologies. Predictive Validity How well do new findings, effects of trial therapeutics predict the effects in humans with the disorder. Kazdoba et al. Curr. Topic. Behav. Neurosci. 2016 Guy et al. Nature genetics 2001 Layer II/III Pyramidal cells MeCP2 KO Normal Kishi & Macklis Mol Cell Neurosci. 2004 Breathing abnormalities MeCP2 Mutant Normal Kron et al. Disease Mod. & Mech. 2014 Rubin • Here are two very open-ended study questions meant to get students thinking very broadly about the topic. – What can brain tumors teach you about normal brain development and function, and how do they do it? – In what ways is brain tumor biology constrained by normal brain biology? 3. Growth regulation: Brain region Adult P53, PTEN, CDKN2A, EGFR, NF1, IDH1, Pediatric H3G34V, p53 H3K27M,p53, ATVR1, PDGFR, BRAF SHH, INI1, BRAF,p53, ATVR1, MYC Glial tumors with many mutations Glial, neuronal, ependymal, choroid plexus tumors with few mutations 4. Brain tumor cells of origin: medulloblastoma Subependymal Germinal Matrices Fink (2006) J Neurosci Miller & Kotzbauer • Name the two proteins/peptides that pathologically accumulate in Alzheimer’s disease • Longer CAG repeat length in Huntington’s disease increases/decreases/does not affect age of disease onset. • Longer CAG repeat length in Huntington’s disease increases/decreases/does not affect age of disease onset. • You have discovered mutations in the noseein gene responsible for a neurodegenerative disease in a family that develops progressive loss of vision. Your genetic studies suggest autosomal recessive inheritance. Which would be the best approach to generate a mouse model for this disorder. A. Transgenic expression of the WT human noseein gene B. Transgenic expression of mutant human noseein gene C. Knockout of the mouse noseein gene • You have discovered mutations in the noseein gene responsible for a neurodegenerative disease in a family that develops progressive loss of vision. Your genetic studies suggest autosomal recessive inheritance. Which would be the best approach to generate a mouse model for this disorder. A. Transgenic expression of the WT human noseein gene B. Transgenic expression of mutant human noseein gene C. Knockout of the mouse noseein gene