Abstract
Notch signaling plays a crucial role in controling the proliferation and differentiation of stem and progenitor cells during embryogenesis or organogenesis, but its regulation is incompletely understood. BLOS2, encoded by the Bloc1s2 gene, is a shared subunit of two lysosomal trafficking complexes, biogenesis of lysosome-related organelles complex-1 (BLOC-1) and BLOC-1-related complex (BORC). Bloc1s2-/- mice were embryonic lethal and exhibited defects in cortical development and hematopoiesis. Loss of BLOS2 resulted in elevated Notch signaling, which consequently increased the proliferation of neural progenitor cells and inhibited neuronal differentiation in cortices. Likewise, ablation of bloc1s2 in zebrafish or mice led to increased hematopoietic stem and progenitor cell production in the aorta-gonad-mesonephros region. BLOS2 physically interacted with Notch1 in endo-lysosomal trafficking of Notch1. Our findings suggest that BLOS2 is a novel negative player in regulating Notch signaling through lysosomal trafficking to control multiple stem and progenitor cell homeostasis in vertebrates.
Highlights
Notch signaling is a highly conserved cell-to-cell signaling pathway and its function in cell-fate determination makes it essential for embryogenesis and organogenesis, including neurogenesis (Traiffort and Ferent, 2015), vasculogenesis (Krebs et al, 2000) and somite segregation (Wright et al, 2011)
We confirmed the replacement of exons 1–4 and null BLOS2 protein in multiple tissues of Bloc1s2À/À neonate mice, while BLOS2 was highly expressed in brain, spleen and intestine in wild-type (WT) neonate mice (Figure 1—figure supplement 1B and C)
This feature is similar to Bloc1s1À/À and snapin knockout mice (Tian et al, 2005; Zhang et al, 2014a) (Supplementary file 1), suggesting that the three shared subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1) and BLOC-1-related complex (BORC) are essential for embryonic development
Summary
Notch signaling is a highly conserved cell-to-cell signaling pathway and its function in cell-fate determination makes it essential for embryogenesis and organogenesis, including neurogenesis (Traiffort and Ferent, 2015), vasculogenesis (Krebs et al, 2000) and somite segregation (Wright et al, 2011). Cortical neurogenesis requires the exquisite coordination of neural progenitor cell (NPC) proliferation and differentiation to generate the complex and functional cerebral cortex, which is precisely regulated in temporal and spatial patterns (Gal et al, 2006; Guillemot, 2005). Notch signaling plays a crucial role in the control of proliferation of NPCs and neuronal differentiation during corticogenesis (Fortini, 2009; Kopan and Ilagan, 2009; Pierfelice et al, 2011). Notch signals activate the expression of basic helix loop helix (bHLH) Hes transcription factors that maintain undifferentiated NPCs by downregulating proneural gene expression (Bertrand et al, 2002; Kageyama et al, 2007; Ohtsuka et al, 2001; Ross et al, 2003).
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