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During mammalian neural development, a wide variety of neurons and glial cells differentiate from common neural progenitor cells (NPCs). Postnatally, some of these cells transform to adult neural stem/progenitor cells which reside in specialized niches where they continue to produce neurons. The mechanisms controlling NPC fate, however, are not fully understood. Microarray analysis of ribosome-enriched transcripts in NPCs revealed a preferential loading of ribosomes with transcripts im- portant for neuronal differentiation. One preferentially loaded transcript is Ankyrin repeat and KH domain-containing protein 1 (ANKHD1). ANKHD1 is a 270 kDa protein that has been shown to play important roles in progenitor cell proliferation, differentiation, and survival. Moreover, it was found to be deregulated in several cancers, including some leukemias. Due to its apparent role in progenitor cell regu- lation, ANKHD1 may also be an important functional regulator in NPCs. However, no function for ANKHD1 in the mammalian brain has been described so far. The present project aims at elucidating the role of ANKHD1 in embryonic and adult neural progenitor cells in mice. We show that ANKHD1 is expressed throughout murine embryonic brain development and in adult neural progenitor cells. Expres- sion can be detected as early as E12.5 and is robust during the course of cortical development. Selective knockdown of ANKHD1 via in utero electroporation in the developing neocortex promotes apical and basal progenitor proliferation and inhibits differentiation into neurons. This phenotype could be rescued by simulta- neous overexpression of human ANKHD1. Similar to NPCs during development, knockdown of ANKHD1 in primary neurosphere cultures of adult NPCs promotes their proliferation and inhibits neuronal differentiation. Deregulation of embryonic and adult neural progenitor cells can lead to the development of brain cancers, such as glioblastoma multiforme. Accordingly, deregulation of ANKHD1 in glioma initi- ating cells influences their proliferative capacity. Together, these results substantiate the relevance of ANKHD1 for controlling proliferation and differentiation of neural progenitors.
|Supervisor:||Martin-Villalba, Prof. Dr. Ana|
|Date of thesis defense:||28 February 2014|
|Date Deposited:||07 Mar 2014 06:58|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||570 Life sciences|