Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
BMC Genomics. 2014 Mar 19;15:206. doi: 10.1186/1471-2164-15-206.
Adult neurogenesis, which is the continual production of new neurons in the mature brain, demonstrates the strikingly plastic nature of the nervous system. Adult neural stem cells and their neural precursors, collectively referred to as neural progenitor cells (NPCs), are present in the subgranular zone (SGZ) of the dentate gyrus, the subventricular zone (SVZ), and rostral migratory stream (RMS). In order to harness the potential of NPCs to treat neurodegenerative diseases and brain injuries, it will be important to understand the molecules that regulate NPCs in the adult brain. The genetic basis underlying NPC proliferation is still not fully understood. From our previous quantitative trait locus (QTL) analysis, we had success in using a relatively small reference population of recombinant inbred strains of mice (AXBXA) to identify a genetic region that is significantly correlated with NPC proliferation in the RMS.
In this study, we expanded our initial QTL mapping of RMS proliferation to a far richer genetic resource, the BXD RI mouse strains. A 3-fold difference in the number of proliferative, bromodeoxyuridine (BrdU)-labeled cells was quantified in the adult RMS of 61 BXD RI strains. RMS cell proliferation is highly dependent on the genetic background of the mice with an estimated heritability of 0.58. Genome-wide mapping revealed a significant QTL on chromosome (Chr) 6 and a suggestive QTL on Chr 11 regulating the number of NPCs in the RMS. Composite interval analysis further revealed secondary QTLs on Chr 14 and Chr 18. The loci regulating RMS cell proliferation did not overlap with the suggestive loci modulating cell proliferation in the SGZ. These mapped loci serve as starting points to identify genes important for this process. A subset of candidate genes in this region is associated with cell proliferation and neurogenesis. Interconnectivity of these candidate genes was demonstrated using pathway and transcriptional covariance analyses.
Differences in RMS cell proliferation across the BXD RI strains identifies genetic loci that serve to provide insights into the interplay of underlying genes that may be important for regulating NPC proliferation in the adult mouse brain.
成人神经发生是指成熟大脑中持续产生新神经元，这表明神经系统具有惊人的可塑性。成人神经干细胞及其前体细胞，统称为神经祖细胞（NPC），存在于齿状回的颗粒下区（SGZ）、脑室下区（SVZ）和额迁移流（RMS）中。为了利用 NPC 治疗神经退行性疾病和脑损伤的潜力，了解调节成年大脑中 NPC 的分子将是很重要的。NPC 增殖的遗传基础尚不完全清楚。从我们之前的数量性状基因座（QTL）分析中，我们成功地使用了一个相对较小的重组近交系小鼠（AXBXA）参考群体来鉴定与 RMS 中 NPC 增殖显著相关的遗传区域。
在这项研究中，我们将 RMS 增殖的初始 QTL 作图扩展到了更丰富的遗传资源，即 BXD RI 小鼠品系。在 61 个 BXD RI 品系的成年 RMS 中，增殖性、溴脱氧尿苷（BrdU）标记细胞的数量差异扩大了 3 倍。RMS 细胞增殖高度依赖于小鼠的遗传背景，遗传力估计为 0.58。全基因组作图显示，Chr6 上存在一个显著的 QTL，Chr11 上存在一个提示性的 QTL，调节 RMS 中的 NPC 数量。复合区间分析进一步揭示了 Chr14 和 Chr18 上的次要 QTL。调节 RMS 细胞增殖的基因座与提示性调节 SGZ 细胞增殖的基因座不重叠。这些定位的基因座是识别对该过程重要的基因的起点。该区域的候选基因子集与细胞增殖和神经发生有关。使用途径和转录协方差分析证明了这些候选基因的连通性。
BXD RI 品系之间 RMS 细胞增殖的差异确定了遗传基因座，这些基因座提供了对潜在基因相互作用的深入了解，这些基因可能对调节成年小鼠大脑中的 NPC 增殖很重要。
