The linkage between cell cycle exit and terminal differentiation represents a critical phase of cellular development. However, very little is known regarding the mechanisms functioning at the growth arrest/differentiation interface in neurons and other cell types. Such mechanisms are likely to play a vital role in not only the onset or establishment of terminal differentiation, but also in the maintenance of its normal irreversibility. Thus, elucidating the mechanisms operating at this critical developmental juncture is also likely to be importance in understanding the etiology and treatment of many forms of cancer. The long-term goal of this proposal is to determine how the events associated with growth arrest are mechanistically linked to transcriptional regulation of specific genes during onset of terminal differentiation and how transcription factors activating these promoters are themselves regulated by growth arrest signals. This proposal focuses on neurogenesis, during which arrest of neuroblasts leads to the """"""""birth"""""""" of postmitotic neurons and the onset of terminal differentiation. This event is a major determinant of which neurons survive and ultimately form the complex wiring of the nervous system, and also is important in establishing the identities of specific neuronal sub-types. An underlying hypothesis is that the mechanisms linking growth arrest and differentiation in neurons are cell lineage-specific. A major goal is to characterize the basis for this neuron-specificity and, in particular, the nature of the regulatory transcription factors involved. These studies will help to reveal the mechanisms controlling neurogenesis during development as well as in the adult nervous system, and in this regard are relevant to potential therapies for neuro-degenerative diseases. Further, they are important for understanding tumorigenesis in general, including neoplasias of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079999-04
Application #
6709401
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (01))
Program Officer
Mietz, Judy
Project Start
2001-03-08
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2006-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$263,940
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Wang, Wei; Crandall, James E; Litwack, E David et al. (2010) Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons. J Neurosci Res 88:258-65
Wang, Wei; Mullikin-Kilpatrick, Debra; Crandall, James E et al. (2007) Nuclear factor I coordinates multiple phases of cerebellar granule cell development via regulation of cell adhesion molecules. J Neurosci 27:6115-27
Wang, Wei; Qu, Qiang; Smith, Frances I et al. (2005) Self-inactivating lentiviruses: versatile vectors for quantitative transduction of cerebellar granule neurons and their progenitors. J Neurosci Methods 149:144-53
Wang, Wei; Stock, Rachel E; Gronostajski, Richard M et al. (2004) A role for nuclear factor I in the intrinsic control of cerebellar granule neuron gene expression. J Biol Chem 279:53491-7
Persengiev, S P; Li, J; Poulin, M L et al. (2001) E2F2 converts reversibly differentiated PC12 cells to an irreversible, neurotrophin-dependent state. Oncogene 20:5124-31