Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging

Abstract

Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used 2-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI Family Zinc Finger 1 (Gli1) or Achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.

Prolonged development of long-term potentiation at lateral entorhinal cortex synapses onto adult-born neurons

“…1A). While tamoxifen labels Ascl1 + precursor cells that may divide at later dates, Ascl1 + cells are typically non-renewing and produce the majority of their neuronal daughter cells within ~2-3 weeks after tamoxifen injection [45,46]. Consistent with relatively precise birthdating, the timecourse of electrophysiological maturation following tamoxifen injection closely parallels that of retrovirally-labelled adult-born granule cells [41].…”

“…First, modelling the timecourse of neuronal maturation in Ascl1 CreERT2 mice suggests that tamoxifen labels a cohort of cells that are largely born around the time of injection [41]. Recent in vivo imaging of Ascl1 CreERT2 mice confirms this, and has indicated that these cells are non-renewing, divide by ~12 days post-injection, and produce the majority of their daughter cells within ~10 days of division [46]. Thus, while there may be some loss of temporal resolution, the majority of cells are generated in a window of time that is much smaller than the timecourse of LTP changes we observed here.…”

Post-stroke Neurogenesis: Friend or Foe?

“…In physiological situations or even in normal aging, different kinds of hippocampal type-1 or radial-glia-like progenitors, called type α-, β-, and -cells, can be distinguished by unique morphological features, specific expression markers and by their proliferative capacity and quiescence (Gebara et al, 2016;Martín-Suárez et al, 2019). Further evidence for this heterogeneity comes from recent single-cell RNA sequencing studies which also shed light on the identity of NSCs residing in the SVZ (Llorens-Bobadilla et al, 2015;Luo et al, 2015;Dulken et al, 2017;Zywitza et al, 2018;Mizrak et al, 2020) or the SGZ (Shin et al, 2015;Artegiani et al, 2017;Berg et al, 2019;Bottes et al, 2020). These studies have provided important clues which reflect the heterogeneous nature of NSCs and NPCs in both niches but also suggest distinctive features of NSCs in the two neurogenic regions.…”

Regulation of Adult Mammalian Neural Stem Cells and Neurogenesis by Cell Extrinsic and Intrinsic Factors

“…Id proteins can directly interact with Hes1 and inhibit the negative autoregulation of Hes1, contributing to sustained quiescence of NSCs [ 37 ]. Moreover, Id4, expressed in quiescent NSCs, sequesters Ascl1 heterodimerization partner E47 and promotes Ascl1 protein degradation [ 15 , 38 , 39 ]. Besides the regulation by Hes1 and Id4, the Ascl1 level is regulated at the protein level by other factors, such as HECT, UBA, and WWE domain containing 1 (Huwe1) [ 35 , 40 ].…”

“…A recent study showed that Ascl1-expressing NSCs mostly divide asymmetrically and generate an NSC and a cell committed toward the neuronal lineage [ 56 ]. This population repeats the asymmetric division a few times within about 10 days, and then eventually, all of the cells turn into neurons [ 38 , 56 , 57 ] ( Figure 2 A). Subsequent studies discovered another population of NSCs, which are expressing Gli1 [ 38 , 43 , 58 ] ( Figure 2 B).…”