Transient amplifying intermediate neural progenitor cells (INPs) play critical roles in boosting neuronal output from neural stem cells (NSCs) and brain tumor formation. It is fundamentally important to understand how the generation and proliferation of INPs is regulated. The long-term goal of this project is to elucidate mechanisms that regulate INP generation and proliferation using the recently identified Drosophila type II neuroblast (NBs, the Drosophila NSC) lineages as a model system. In Drosophila larval brains, self-renewing INPs are generated from the type II NBs but not the classical type I NB. Furthermore, due to additional INP-mediated amplification of NB proliferation, type II NB lineages are extremely susceptible to tumorigenesis. However, why only type II NBs but not type I NBs generate INPs was totally unknown. My recent work identified the first molecule, the evolutionally conserved Ets family transcriptional activator Pointed P1 (PntP1), which is specifically expressed in type II NB lineages and is both necessary and sufficient to promote INP generation. Furthermore, my work demonstrated that PntP1 is the key molecule responsible for the susceptibility of type II NB lineages to tumorigenesis. The objective of this project is to elucidate the function and mechanisms of a potential PntP1 target gene, buttonhead (btd), in regulating INP generation, brain complexity, and brain tumor formation. The central hypothesis is that Btd functions downstream of PntP1 to promote INP generation and increase neural diversity by preventing Pros-mediated premature differentiation of INPs and that Btd contributes to tumorigenesis in type II NB lineages. We will test the hypothesis by pursuing following three specific aims. 1) Determine whether and how Btd functions downstream of PntP1 to promote INP generation;2) Investigate the role of Btd in generating neural diversity;3) Define the function of Btd in tumorigenic overproliferation of type II NBs. The proposed project is expected to reveal novel mechanisms that control INP generation, brain complexity, as well as brain tumor formation.

Public Health Relevance

Transient amplifying intermediate neural progenitor cells (INPs) are critical for generating brain complexity. Defects in generating INPs can result in severe developmental neurological disorders such as microcephaly and cortical malformations, whereas unrestricted proliferation of INPs can lead to brain tumor formation. Therefore, deciphering molecular mechanisms that control INP generation will not only help us understand how various developmental neurological disorders and brain tumors develop, but will also provide much needed knowledge for designing novel therapeutic treatments of these neurological diseases as well as other neurodegenerative diseases and brain/spinal cord injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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Upstate Medical University
Other Basic Sciences
Schools of Medicine
United States
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