In higher eukaryotes, certain tissues consist of a special type of cells known as stem cells. Stem cells divide to self-renew and at the same time to generate a progeny that is committed to a differentiation pathway. Although of much importance, very little is known of how a stem cell acquires its identity or how it functions. In Drosophila, the primary neuronal precursor cells (Neuroblasts, NB) function as stem cells and divide by self-renewing asymmetric mitosis. During neurogenesis, a NB self-renews and also produces a chain of ganglion mother cells (GMCs). A GMC is bipotential, it does not self-renew but divides asymmetrically to generate two distinct post-mitotic neurons. Thus, from -30 NBs in a given hemisegment, -320 distinct neurons are generated. This indicates that the ability of NBs to function as stem cells and the ability of NBs and GMCs to divide by asymmetric mitosis is crucial in generating a large number of neurons from a few precursor cells. Our long-term goal aims to explore the genetic regulation of self-renewing stem cell type of asymmetric divisions using the Drosophila CNS as our model system. In order to study the problem of self-renewing and terminal asymmetric divisions, we have selected several different CNS lineages: MP2, NB7-3, GMC-1->RP2/sib, and GMC-1->aCC/pCC lineages. During the past several years, we have identified through genetic screens mutations that show self-renewing and terminal asymmetric division in one or more of these lineages. In this grant we propose to further study these mutations. Thus, our specific aims include: (1) To investigate the role of Midline in inhibiting the self- renewing asymmetric division potential of neural precursor cells, and, 2) To determine how Neuralized-like inhibits the self-renewing asymmetric division potential of precursor cells, and 3) To determine the role of Polycomb, a chromatin re-modeling protein, in the asymmetric division of GMCs. These studies will help understand pathways that govern the self-renewing and terminal asymmetric division of precursor cells in multi-cellular organisms. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Zatz, Marion M
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Bhat, Krishna Moorthi (2014) Notch signaling acts before cell division to promote asymmetric cleavage and cell fate of neural precursor cells. Sci Signal 7:ra101
Poddighe, Simone; Bhat, Krishna Moorthi; Setzu, Maria Dolores et al. (2013) Impaired sense of smell in a Drosophila Parkinson's model. PLoS One 8:e73156
Manavalan, Mary Ann; Gaziova, Ivana; Bhat, Krishna Moorthi (2013) The midline protein regulates axon guidance by blocking the reiteration of neuroblast rows within the Drosophila ventral nerve cord. PLoS Genet 9:e1004050
Zhu, Zengrong; Bhat, Krishna Moorthi (2011) The Hem protein mediates neuronal migration by inhibiting WAVE degradation and functions opposite of Abelson tyrosine kinase. Dev Biol 357:283-94
Bhat, Krishna Moorthi; Gaziova, Ivana; Katipalla, Sumana (2011) Neuralized mediates asymmetric division of neural precursors by two distinct and sequential events: promoting asymmetric localization of Numb and enhancing activation of Notch-signaling. Dev Biol 351:186-98
Zhu, Zengrong; Bhat, Krishna Moorthi (2011) The Drosophila Hem/Kette/Nap1 protein regulates asymmetric division of neural precursor cells by regulating localization of Inscuteable and Numb. Mech Dev 128:483-95
Hafer, Nathaniel; Xu, Shuwa; Bhat, Krishna Moorthi et al. (2011) The Drosophila CPEB protein Orb2 has a novel expression pattern and is important for asymmetric cell division and nervous system function. Genetics 189:907-21
Bhat, Krishna Moorthi (2007) Wingless activity in the precursor cells specifies neuronal migratory behavior in the Drosophila nerve cord. Dev Biol 311:613-22