Transcriptional regulation of neural stem cell expansion in the adult hippocampus

Abstract

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell-cycle, fatty acid oxidation and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

Multi-omic analysis of guided and unguided forebrain organoids reveal differences in cellular composition and metabolic profiles

“…Astrocyte mitochondria are enriched with enzymes involved in mitochondrial β-oxidation of fatty acids and metabolise long chain fatty acids more efficiently than neuronal mitochondria 50,51 . However, studies also suggest that fatty acid β-oxidation is key for neural stem cell self-renewal 52,53 . As such the larger proportion of radial glia in day 40 unguided FOs determined by scRNAseq, and supported by increased GFAP levels, could also be a potential source of the increased fatty acid β-oxidation enzymes and metabolites.…”

Role and limitation of cell therapy in treating neurological diseases

“…Neurodegenerative diseases, colloquially termed the “silent killers” within the geriatric demographic, predominantly involve the loss of neurons, a phenomenon further compounded by the heightened susceptibility inherent in mature nervous systems 4,19 . NSCs, residing within the central nervous system, possess the capacity to generate diverse neural components, encompassing neurons, astrocytes, and oligodendrocytes 16,20 . Predominantly localized in regions, such as the subventricular zone, dentate gyrus of the hippocampus, and the hypothalamus, NSCs assume a pivotal role in the therapeutic management of neurodegenerative diseases, 21–23 and manifest the capability to undergo differentiation into a spectrum of cell types, including neurons, astrocytes, and oligodendrocytes 24 .…”

YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory

“…To test whether and how the m 6 A readers YTHDF1 and YTHDF2 work in specific hippocampal subregions to regulate hippocampus-dependent learning and memory, we sought to generate subregion-specific conditional knockouts (cKO) of these proteins. For this purpose, we chose Pomccre 18 , Grik4-cre 19 , and Camk2α-cre (T29-1) 20 lines, which have been used by multiple studies to do DG-, CA3-, or CA1-specific analysis, respectively [18][19][20][21][22][23][24][25][26] . By crossing with the Rosa26-eYFP reporter 27 , we validated the hippocampal subregion-specific expression of these Cre lines (Supplementary Fig.…”