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• Last Lecture – Molecular pathways to select a single neuroblast from proneural cluster Lect 5 • Today – Neuroblast → neuron (or glia) – D/V patterning – Anterior/posterior patterning Neuroblast formation in Drosophila Prepatterning Proneural Clusters Single Cells selected to become neurons & inhibit neighbours Neurons Specifying neuronal type Ganglion Mother CellII (GMCII) Ganglion Mother CellI (GMCI) Neuroblast Dorsal-Ventral Patterning genes Proneural genes Neurogenic genes 1 Asymmetric Cell Division leads to generation of neurons Neurons or glia GMCI NB GMCI GMCII GMCI GMCII GMCIII NB NB What controls NB vs GMC identity • Neuroblast vs. GMC – Asymmetric localization of prospero and numb at cell division • prospero and numb go into GMC and are excluded from NB • prospero and numb are important for maintaining GMC fate, and repressing NB fate • Mechanism involves actin cytoskeleton NB & prospero • At cell division – Numb and Prospero become localized to the GMC – Inscuteable orients the mitotic spindle – Proteins such has Miranda, move along actin cytoskeleton to opposite pole – Miranda binds to Numb and Prospero – Numb and Prospero specify GMC • Numb inhinits Notch signalling pathway 2 CSN neuroblasts PNS neurons Prospero Green = numb Red = DNA Actin DNA Spana & Doe, 1995 • Mutants of prospero – Failure to express “GMC genes” – Incorrect cell lineage • Prospero also required for glial vs neural lineage – prospero can activate expression of glial cells missing (gcm) – gcm is a master regulator gene for glial cell fate gcm- glia U neurons gcm+ 3 Short Summary • Drosophila Neurogenesis 1. 2. 3. 4. 5. 6. Dorsal ventral pattern (dpp, sog) Establishing neurogenic region (SoxN) Activation of proneural genes (A-SC) Selection of neuroblast (Notch signaling) Identity of GMC Glial cell fate • How to get specific neurons 1. Dorsal / ventral patterns within the nervous system 2. Anterior / posterior patterns 1b. D/V patterning of neural tube Dorsal Neural tube Neural plate Ventral Transcription factors in NB change over time 1a – in flies, the GMCs inherit transcription factor profile of the NB at the time of cell division mesoderm notochord Vertebrate embryo 4 D/V patterning of neural tube Control Remove Notochord Extra Notochord What is notochord signal? Sonic Hedgehog neurons Floor plate Text Fig 2.17 Implies a signal from notochord to neural tube Jessell, 2000, Nature Reviews Genetics • Sonic Hedgehog – Secreted protein Subtypes of interneurons – Different concentrations of Shh induce different types of neurons – Shh regulates expression of 6 different transcription factors based on concentration gradient Motor neurons interneurons Jessell, 2000, Nature Reviews Genetics – Combination of transcription factors defines which type of neuron will develop 5 Fig 2.22 D/V patterning of neural tube BMPs Shh +Shh +BMP +Shh BMPs Ventral markers Shh Dorsal markers BMPs suppress Shh-induced ventral • Antagonism of BMPs and Shh – Opposing gradients control the dorsal ventral polarity of the spinal cord and cell fates along the D/V axis • Shh – Activates transcription factors that identify unique groups of neurons Shh MNR2 ISL1 Motor neurons 6 How to get specific neurons 2. Anterior posterior postion – Anterior posterior patterning – Homeobox genes – Combinatorial signaling Anterior-Posterior Patterning – In most animals the head looks different than the tail! – In most animals the body of the animal is segmented • Think spinal column / vertebrae Bic • Again, look at patterning of Drosophila embryo nanos 1. Gradients of Maternal Products in the egg 2. Gap genes • Kruppel hunchback because there are gaps in there expression pattern Eve ftz 3. Pair-rule genes • because expressed in pairs of segments en 4. Segment polarity genes • Specify anterior / posterior boundaries of individual segments 7 • Maternal genes – define global A/P axis • Gap genes – subdivide embryo into broad regions • Pair-rule genes – broad stripes define an initial repeat of 2 segments • Segment polarity genes – Further subdivide segments into compartments 8