Abstract
BackgroundAdult 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.ResultsIn 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.ConclusionsDifferences 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.
Highlights
Adult neurogenesis, which is the continual production of new neurons in the mature brain, demonstrates the strikingly plastic nature of the nervous system
Whole genome mapping and composite interval analyses revealed secondary quantitative trait locus (QTL) influencing cell proliferation in the rostral migratory stream (RMS). To determine whether these suggestive loci interact with the major Chr 6 locus at the molecular level, we further examined the candidate genes residing in the suggestive QTLs
Whole-genome scan likelihood ratio statistic (LRS) plot generated from QTL mapping of the unadjusted subgranular zone (SGZ) cell proliferation data (B) and the adjusted data corrected for age effects (C)
Summary
Adult neurogenesis, which is the continual production of new neurons in the mature brain, demonstrates the strikingly plastic nature of the nervous system. The persistent division of neural progenitor cells (NPCs) and the production of new neurons in the adult brain raise hope for potential therapies targeting the NPCs to compensate for neuronal loss in injured or disease brains. This process of continual neuron production, known as adult neurogenesis, occurs in discrete brain regions that. A number of morphogens including Wnt, Notch, Sonic hedgehog, and Ephrins have been shown to regulate cell proliferation in the adult SVZ [7] External stimuli such as age, exercise, sleep, and stress have been shown to influence NPC proliferation [10,11,12]. The genetic basis of NPC proliferation, is not fully understood
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