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Genetic architecture of neurogenesis in the adult mouse forebrain : insights from quantitative trait locus analyses

University of British Columbia

Neural stem cells and their precursors, collectively referred to as neural progenitor cells (NPCs), are present in discrete regions of the mature brain, namely the subgranular zone (SGZ) of the dentate gyrus, the subventricular zone (SVZ), and rostral migratory stream (RMS). These NPCs divide and give rise to new neurons in a process called adult neurogenesis. Genetic influence is a major determinant of adult neurogenesis. However, the genetic architecture underlying NPC proliferation and differentiation is poorly understood. My thesis aims to gain insights into the genes regulating NPC proliferation using a phenotypic-driven, genome-wide approach. I first examined nine inbred mouse strains housed in the same condition and across different ages from 60 days (P60) to 2 years. Wide inter-strain differences and negative impact of age on the number of NPCs were observed in the RMS. Genetic background had a significant effect on NPC proliferation and it also differentially influenced the effect of age on this process. The most dramatic inter-strain difference was detected at P60. Heritability estimated ~50% of the differences in NPC numbers were attributed to the genetic variation among the strains. I used quantitative trait locus (QTL) mapping to survey the entire genome for chromosomal segments referred to as QTLs that contribute to the phenotypic differences. Two panels of recombinant inbred strains, AXB/BXAs and BXDs, were employed for QTL mapping. Genetic variation in QTLs on chromosome (Chr) 6 and 11 were significantly associated with the differences in NPC numbers in the RMS. Additional analyses revealed potential interaction of Chr 6 QTL with other loci. These QTLs are hypothesized to harbor genes important for NPC proliferation and downstream experimentation is required to validate the function of these genes. As proof of concept, a candidate gene called Galanin receptor 2 (Galr2) in the Chr 11 QTL was demonstrated to be a pro-proliferative regulator of NPCs using in vitro techniques manipulating Galr2 expression and Galr2 knockout mice. In summary, I identified novel QTLs underlying NPC proliferation and these loci serve as starting points to identify genes (e.g. Galr2) critical to this process.

Text

2014-09-16

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/50395

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/