Usp9x-deficiency disrupts the morphological development of the postnatal hippocampal dentate gyrus

Abstract

Within the adult mammalian brain, neurogenesis persists within two main discrete locations, the subventricular zone lining the lateral ventricles, and the hippocampal dentate gyrus. Neurogenesis within the adult dentate gyrus contributes to learning and memory, and deficiencies in neurogenesis have been linked to cognitive decline. Neural stem cells within the adult dentate gyrus reside within the subgranular zone (SGZ), and proteins intrinsic to stem cells, and factors within the niche microenvironment, are critical determinants for development and maintenance of this structure. Our understanding of the repertoire of these factors, however, remains limited. The deubiquitylating enzyme USP9X has recently emerged as a mediator of neural stem cell identity. Furthermore, mice lacking Usp9x exhibit a striking reduction in the overall size of the adult dentate gyrus. Here we reveal that the development of the postnatal SGZ is abnormal in mice lacking Usp9x. Usp9x conditional knockout mice exhibit a smaller hippocampus and shortened dentate gyrus blades from as early as P7. Moreover, the analysis of cellular populations within the dentate gyrus revealed reduced stem cell, neuroblast and neuronal numbers and abnormal neuroblast morphology. Collectively, these findings highlight the critical role played by USP9X in the normal morphological development of the postnatal dentate gyrus.

USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus

“…15 Interestingly, when we examined the proportion of NSCs that were quiescent versus those that were proliferating, we found a significantly higher proportion of proliferating NSCs in the SGZ of Usp9x-deficient mice, and a concomitant decrease in the proportion of quiescent NSCs, compared to controls. 15 Together, these findings indicate that Usp9x-deficiency culminates in abnormal neurogenesis within the postnatal SGZ, which contributes to, at least in part, the reduced size of the dentate gyrus. However, it remains unclear as to why the lack of Usp9x leads to an increase in the relative proportion of proliferating NSCs within the SGZ but a reduced number of neuronal cells in the dentate granule cell layer.…”

“…13 The conditional ablation of Usp9x from NSCs within the embryonic forebrain (via Emx1-Cre-mediated deletion) results in a number of cortical abnormalities, 14 most notably the severe reduction in the size of the postnatal hippocampus and dentate gyrus, evident as early as one week after birth. 15 We recently analyzed cellular populations within the postnatal dentate gyrus of these Usp9x-deficient mice and showed a significant decrease in the total number of NSCs, neuroblasts and mature neurons. 15 Interestingly, when we examined the proportion of NSCs that were quiescent versus those that were proliferating, we found a significantly higher proportion of proliferating NSCs in the SGZ of Usp9x-deficient mice, and a concomitant decrease in the proportion of quiescent NSCs, compared to controls.…”

“…15 We recently analyzed cellular populations within the postnatal dentate gyrus of these Usp9x-deficient mice and showed a significant decrease in the total number of NSCs, neuroblasts and mature neurons. 15 Interestingly, when we examined the proportion of NSCs that were quiescent versus those that were proliferating, we found a significantly higher proportion of proliferating NSCs in the SGZ of Usp9x-deficient mice, and a concomitant decrease in the proportion of quiescent NSCs, compared to controls. 15 Together, these findings indicate that Usp9x-deficiency culminates in abnormal neurogenesis within the postnatal SGZ, which contributes to, at least in part, the reduced size of the dentate gyrus.…”

“…USP9X promotes the self-renewal of embryonic stem cell-derived NSCs in vitro. 13 In vivo, USP9X is highly expressed throughout the developing central nervous system, 14 the postnatal hippocampus, 15 and within the adult neurogenic niches. 13 The conditional ablation of Usp9x from NSCs within the embryonic forebrain (via Emx1-Cre-mediated deletion) results in a number of cortical abnormalities, 14 most notably the severe reduction in the size of the postnatal hippocampus and dentate gyrus, evident as early as one week after birth.…”

“…15 Validation of these microarray data was performed using quantitative polymerase chain reaction (qPCR) on cDNA generated from mRNA isolated from independent hippocampal samples from P14 mice. This analysis confirmed that the relative expression of these oligodendrocyte-associated genes was significantly elevated in mutant samples compared to controls (Fig.…”