Date of Completion

7-5-2016

Embargo Period

7-6-2018

Advisors

Andrew Moiseff, Joseph Crivello, David Goldhamer

Field of Study

Physiology and Neurobiology

Degree

Master of Science

Open Access

Open Access

Abstract

Microcephalic osteodysplastic primordial dwarfism type-1 (MODI) is a rare congenital developmental disorder resulting in patients presenting with microcephaly, limb abnormalities, and growth retardation. This disease, along with the related Roifman Syndrome, results from mutations to the gene RNU4atac. This gene encodes for the U4atac small nuclear RNA (snRNA) which, along with four other snRNAs (U11, U12, U5, and U6atac) compose the small nuclear ribonucleoprotein (snRNP) complex called the minor spliceosome. Responsible for the excision of a subpopulation of introns (called minor introns), the minor spliceosome is known to play an essential role in eukaryotic limb development. However, while mutations in RNU4atac have been shown to decrease efficiency of minor splicing, a direct role of minor splicing in limb development has thus far only been implicated. Utilizing a RNU11 conditional knockout mouse, I demonstrate through a non-U4atac dependent animal model that minor splicing is required for proper development of the murine limb. Using skeletal analysis I reveal that minor splicing results in compromised development of the mouse limb, and that the severity of this developmental disruption increases along the proximodistal axis. Additionally, utilizing TUNEL assays alongside immunofluorescence I demonstrate that that minor splicing may play a role in maintenance of the proliferating progenitor cell population within the developing mouse limb.

Major Advisor

Rahul Kanadia

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