The long-term goal of this application is to understand the molecular control of neuronal specification and differentiation in the cerebellum. The cerebellum is a midbrain-hindbrain structure that participates in coordination of motor function and higher cognition function. Abnormal cerebellar development can lead to neurological diseases such as autism and medulloblastoma. Although the morphogenesis of cerebellum has been well studied in the past century, little is known about the molecular mechanisms that control the fate specification and differentiation of the cerebellar neurons and their associated precerebellar neurons located in the brainstem. Recent studies have demonstrated that transcription factors of the bHLH family are important regulators of the proliferation, fate specification and differentiation of cerebellar neurons and precerebellar neurons. In this application, we propose to study the functional role of Olig3 bHLH factor in the development of cerebellar and precerebellar neurons. During early neural development, Olig3 is highly expressed in the rhombic lips of the hindbrain, the dorsal neural progenitor cells that give rise to both cerebellar neurons and precerebellar neurons. The pattern of Olig3 expression leads us to hypothesize that it functions to regulate the development of cerebellar system. In this pilot application, two specific aims are proposed to test this hypothesis and further define its role in the fate specification, proliferation, migration or differentiation of cerebellar and precerebellar neurons.
The first aim of the proposal is to characterize the mutational effects of Olig3 on the specification and differentiation of cerebellar nd precerebellar neurons.
The second aim i s to investigate possible changes in the identity and migration of rhombic lips cells in Olig3 mutant embryos using the Cre-loxP mediated genetic labeling methods. ?

Public Health Relevance

The proposed studies will provide important insights into the molecular regulation of neuronal specification, proliferation and differentiation in the developing cerebellar system. Knowledge obtained from this study can help us understand the molecular mechanisms underlying cerebellum disorders and medulloblastoma and provide cues for therapeutic treatment of these neurological diseases. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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Zheng, Kang; Li, Hong; Zhu, Ying et al. (2010) MicroRNAs are essential for the developmental switch from neurogenesis to gliogenesis in the developing spinal cord. J Neurosci 30:8245-50
Liu, Zijing; Li, Hong; Hu, Xuemei et al. (2008) Control of precerebellar neuron development by Olig3 bHLH transcription factor. J Neurosci 28:10124-33