Cell Fate Determination in the Cerebellum

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DESCRIPTION (provided by applicant): Neural development requires that a series of cell types be produced in a tightly subscribed temporal sequence. In this regard the cerebellar rhombic lip is of particular interest. While originally considered to give rise only to granule cells, it is now known to also contribute to a variety of hindbrain nuclei, as well as the deep cerebellar nuclei. Our previous work demonstrated that through an interplay between Notch and BMP signaling, cerebellar ventricular zone cells are sequentially recruited to become Mathl-expressing rhombic lip progenitors. Remarkably, genetic fate mapping has revealed that the Mathl expressing progenitors within the rhombic lip are highly transient, such that lineally distinct Mathl populations sequentially give rise to hindbrain and deep cerebellar nuclei between E10 and E12 and cerebellar granule cells between E12 and E16. In the first part of this grant we will explore which populations within the cerebellar ventricular zone give rise to the sequential cohorts of Mathl positive rhombic lip progenitors. Furthermore during this progressive induction period, we will examine the identity and progeny derived from Notch versus BMP responsive precursors. In the final part of this aim we will examine whether there exists covert lineage compartments within the rhombic lip. Specifically, we will determine whether specific hindbrain subtypes (e.g. Chat-+ve hindbrain neurons) are produced within a particular medio-lateral domain of the rhombic lip. In the second section of this grant, we test our hypothesis that Mathl acts in conjunction with three transcription factors, Id4, Tbr2 and Pax6 to control the competence of the rhombic lip to produce discrete neuronal subtypes. We will first examine whether the persistence of Mathl in late but not early rhombic lip progeny affects their competence. We will next do a loss of function analysis of either null or conditionally null alleles of Id4, Tbr2 and Pax6. Finally we will use an inducible gain of function approach to test the sufficiency of these genes to cell autonomously affect the fate of rhombic lip progenitors. Together these studies will not only be informative in revealing how Mathl shapes development in the hindbrain and cerebellum but will also provide insight into how the examined downstream transcription factors direct cell fate in this region. Relevance to Public Health: Disfunction in the cerebellum and hindbrain is responsible for a wide spectrum of neurological disorders including dyskinesia, ataxia and autism. Key neuronal populations implicated in these disease states are generated within the rhombic lip. Our studies will reveal the mechanisms by which these populations are generated and thus provide the first step towards finding a cure to these disorders.