HOPX Defines Heterogeneity of Postnatal Subventricular Zone Neural Stem Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionGerminal activity persists in the postnatal mammalian brain in specialized niches, namely the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) that surrounds the lateral ventricle (LV). Neural stem cells (NSCs) of the postnatal SVZ divide and give rise to transient amplifying progenitors (TAPs) that generate neuroblasts, which migrate via the rostral migratory stream (RMS) into the olfactory bulb (OB), where they differentiate into neurons (). The SVZ additionally generates glial progenitors that invade the local parenchyma (reviewed in ). Recently, accumulating evidence has highlighted the heterogeneous nature of postnatal SVZ in respect to different microdomains generating distinct neural lineages. For example, progenitors of GABAergic neurons are predominantly derived from the lateral SVZ (lSVZ), while the genesis of glutamatergic neuron progenitors is restricted to the dorsal SVZ (dSVZ; ; reviewed in ). Furthermore, postnatally derived oligodendrocytes are generated from the dSVZ (). This heterogeneity originates from early embryonic development (), and is intrinsically encoded by expression of selected transcription factors (TFs). Therefore, TFs enriched in specific embryonic forebrain regions are persistent in their expression in corresponding microdomains of the postnatal SVZ. Examples of such TFs include EMX1 (pallium; dSVZ), GSX1/2 (lateral and medial ganglionic eminence; lSVZ), and ZIC1/3 (septum; medial SVZ; reviewed in ). We recently resolved the transcriptional heterogeneities of different cell populations of the postnatal SVZ, in which an unexpected large number of transcripts (i.e. 1900) were differentially expressed in NSCs and TAPs sorted from defined SVZ microdomains. Intriguingly, most of the transcriptional heterogeneity observed between the dorsal and lateral NSCs (dNSCs and lNSCs) was due to the expression of transcriptional cues. Notably, HOPX was identified with specific abundant expression in dNSCs (). HOPX is a small (73 amino acids) atypical homeodomain protein that lacks DNA binding sites (, ). Hopx expression is minimal at embryonic day 14.5 (E14.5) and peaks around E16.5 with a rostromedial to caudolateral gradient (). HOPX expression has been found in radial astrocytes of the adult DG, while it is described to be consistently absent from the adult SVZ (). Moreover, the expression of HOPX has recently received increasing attention due to its expression in quiescent NSCs, in mature astrocytes in the adult mouse DG (), as well as in outer radial glia (oRG) cells of the developing human brain (, ). Here, we used various approaches to further investigate the regionalization of the postnatal SVZ and of resident subpopulations of NSCs. In particular, we characterized the spatiotemporal and lineage-specific patterns of HOPX expression in the postnatal SVZ and investigated its potential function in postnatal SVZ germinal activity.