Development of stem cell lineages in the Drosophila CNS and germline.
Generation of a complex nervous system that can carry out such extraordinary functions as higher order thinking is a problem of critical importance. Studies in the past several years have shown that during neuronal development a large diversity of cell types is generated in a highly stereotyped spatial and temporal pattern. These studies have also shown that the multipotential, neuronal progenitor cells undergo a series of asymmetric cell divisions to self renew and to generate several rounds of neurons of distinct identities. Thus, a complex array of different cell types is formed from relatively few precursor stem cells. In higher eukaryotic organisms, stem cells are involved in constituting a number of lineages, such as the skin, intestinal epithelia, the immune system and the nervous system. 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. Our long term goal is to understand 1) the mechanisms that govern the development and functioning of the stem cell lineages in the CNS of the fruit fly Drosophila, and 2) the regulation of nervous system development in the ventral nerve cord of the Drosophila embryo.
The relatively simple CNS of the Drosophila embryo provides an experimentally advantageous model system for investigating the mechanisms that generate and pattern the eukaryotic nervous system. In the Drosophila embryo, within the developing CNS hundreds of different cell types are generated from a relatively uniform two dimensional epithelial sheet. During neurogenesis, about 30 neuroblast (NB) cells delaminate from this sheet in each half segment. A NB functions as a stem cell and divides by asymmetric mitosis to self-renew and to produce a chain of ganglion mother cells (GMCs). A GMC, though pluripotential, does not self-renew; instead it divides asymmetrically to generate two distinct neurons. At the end of neurogenesis, each half segment is thought to contain ~320 distinct and highly specialized neurons. These studies indicate 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 of distinct identities. Our long term goal is to elucidate at the molecular level mechanisms that govern cell identity specification and asymmetric cell division at each level of neuronal lineage elaboration (NB, GMC) in the CNS of Drosophila.
We have selected a typical neuroblast stem cell lineage, the NB4-2 lineage, that generates the RP2 motoneuron and its sibling cell RP2-sib (NB4-2-->GMC-1->RP2/sib), in the ventral nerve chord to study the problems of cell identity specification and asymmetric cell division during neurogenesis. Using the power of Drosophila genetics, we have identified by genetic screens well over 50 new point and deletion mutations that perturb the development of the NB4-2-->GMC-1->RP2/sib lineage. These mutations can be categorized into those which cause: loss of RP2s, gain of RP2s, loss and gain of RP2s, division defects, migration defects and special types of defects. These reveal many novel aspects of the elaboration of a neuroblast stem cell lineage. We have selected a subset of these mutations for investigating questions such as, how do neuroblast stem cells self-renew and at the same time generate progeny that are commit
People Krishna Bhat (Principal Investigator)
Erik van Beers
Adam Berger
Bidong Truong
Jennifer Waters
Grants Work in my laboratory is supported by a grant from NIH (R01GM58237)(1998-2003)
Positions available Positions at the level of post-doctoral associates, graduate students and undergraduate students (work/study) are available
