Neurogenin1 Expression and Function in the Developing Mouse Cerebellum

Abstract

The basic helix-loop-helix (bHLH) transcription factors Ptf1a and Math1 are necessary for the specification of gamma-aminobutyric acid (GABA)-ergic and glutamatergic cell lineages in the cerebellum, respectively. Recent evidence suggests that cascades of bHLH factor activities drive cell type specificity in Ptf1a-positive and Math1positive lineages. Neurogenin1 (Neurog1) is a bHLH transcription factor involved in the development of several nervous system structures including the cerebral cortex, trigeminal sensory neurons, inner-ear sensory neurons, and olfactory sensory neurons.Recently, expression of Neurog1 has been reported to be co-expressed in Ptf1aexpressing cells in the ventricular zone (VZ) of the developing cerebellum, suggesting a role in subtype specification of GABAergic progenitor cells.Using immunohistochemistry and transgenic reporter mice, we have demonstrated that Neurog1 is expressed during a prolonged period of cerebellar development that spans embryonic and postnatal phases of neurogenesis. Neurog1 is expressed in neuronal cell lineages of the cerebellar cortex, primarily by GABAergic cell lineages. However, Neurog1 is also expressed in small populations of glutamatergic unipolar brush cells and by a very limited number of granule cells.Using inducible reporter mice, we have determined the temporal sequence of Neurog1-fated progenitors. Neurog1-fated progenitors first specify Purkinje cells in the xii DEDICATIONOne of life's greatest gifts is the opportunity to freely pursue personal ambitions and find satisfaction in the achievement of them. I feel privileged to have had this opportunity to earn an advanced degree in neuroscience while exploring the mysteries of the brain and its development. My gratitude is deepened and my resolve to make the most out of life strengthened when I reflect upon the shortened lives of several fellow classmates from my hometown of Spanish Fork, Utah. Although they did not live long enough to fully persue their hopes and dreams their memory remains in those who knew them. And if nothing else that memory inspires us to seize every moment. This dissertation is dedicated to them, their parents, and family members.