Friday, April 26, 2024
4/26/2024
DESCRIPTION (provided by applicant): The inferior olivary nucleus (ION) is one of the principle inputs into cerebellar Purkinje cells and is involved in regulating movement and gaze. Defects in ION formation have been documented in association with a number of inherited ataxic syndromes, autism, fetal alcohol syndrome, and sudden infant death syndrome (SIDS), the leading cause of infant mortality in the United States. Understanding the molecular cues that regulate the formation of this nucleus could provide insight into the etiologies of these syndromes. The progenitor cells that generate the neurons of the ION have been localized to the caudal extent of dorsal regions of the embryonic hindbrain neural tube inclusive of an anatomical region known as the lower rhombic lip (LRL). Progenitors within the LRL are arranged along the dorso-ventral (D/V) axis into molecularly distinct domains that are predictive of future cell fate. While the relative location of ION progenitors has been mapped to ventral regions of the caudal LRL, their exact molecular identity is still under investigation. Increasing evidence indicates that multiple transcription factors acting within the dorsal hindbrain neural tube may contribute to the production and deployment of ION neurons. These factors include the basic helix-loop-helix transcription factors Ngn1, Mash1, and Ptf1a, which are organized into three discreet domains in the LRL. In Aim 1, an in vitro hindbrain electroporation technique will be employed to identify molecular factors responsible specifying ION fate. The progenitors that generate the ION are susceptible to the teratogenic influences of all-trans retinoic acid (atRA)- exogenous introduction of atRA during the developmental window over which these neurons are born results in a dramatic increase in the size of the ION along the rostral-caudal axis. An intriguing explanation for this result is that atRA influences factors (such as the hox genes) that restrict the ION progenitors along that antero-posterior axis. Aim 2 will then use the combined analysis of atRA injected animals and in vitro hindbrain electroporation of constructs corresponding to hox genes and retinoic acid regulatory enzymes to assess the ability of atRA and hox gene boundaries to limit the climbing fiber progenitors along the A/P axis. Together these experiments will address the identity of molecular factors that regulate ION specification along the D/V and A/P axis. PUBLIC HEALTH RELEFANCE: Neurologically based diseases such as ataxia, fetal alcohol syndrome, and sudden infant death syndrome (SIDS) all are characterized by the selective vulnerability of neurons comprising major brain regions, such as the inferior olive. In general, cell type - or brain region-specific vulnerabilities that ultimately lead to disease typically reflect specific properties unique to those cells that are acquired during their development and differentiation. The experiments proposed in this study are aimed at uncovering the molecular signals underlying the development and differentiation of neurons of the inferior olive.
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