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    • It is interesting that OB

    2018-10-20

    It is interesting that OB neurons produced from the transient Gli1-enriched subcallosal domain in juvenile mice mostly corresponded to sGCs, when they were derived from a region with active SHH signaling. It is possible that the relative levels of SHH signaling are adjusted in different domains. The intensity of Gli1 expression (Figure 1) suggests higher levels ventrally than dorsally, but further quantitative analysis of SHH signaling would be required to understand how neuronal cell types are specified. Location in the V-SVZ might be associated not only with differences in SHH signaling levels, but also other signaling pathways. Similarly, high SHH signaling in V-SVZ progenitors is not always associated with high oligodendrogenesis; the ventral V-SVZ has high Gli1 expression, but produces few oligodendrocytes postnatally (Kessaris et al., 2006; Menn et al., 2006). These results reveal a dorsal domain in the juvenile telencephalon with high levels of SHH signaling, where many oligodendrocytes are produced. While our study provides evidence that this transient and restricted domain is an important source of OPCs, we cannot rule out that other regions within the Emx1 dorsal forebrain (Kessaris et al., 2006) could also contribute to oligodendrogenesis. Together with other studies (Merkle et al., 2007, 2014), this work illustrates the high level of regionalization in the postnatal V-SVZ. It will be interesting to determine whether the developing human gli1 contains a similar Gli1-expressing territory. The production of large numbers of OPCs from a similar subcallosal territory could help explain the developmental origin of the many oligodendrocytes required for the greatly expanded white matter in the human brain. Gliomas can originate from OPCs (Alcantara Llaguno et al., 2009; Jacques et al., 2010; Liu et al., 2011); the territory of heightened OPC production we describe here could also help better understand the origin of some brain tumors.
    Experimental Procedures
    Author Contributions
    Acknowledgments We are grateful to Dr. A. Ruiz I Altaba for the ISH probe for Gli1. This work is sponsored by grants from the NIH (HD032116 and NS028478) and a generous gift from the JG Bowes Foundation. A.A.-B. is the Heather and Melanie Muss Endowed Chair. L.C.F. is a HHMI fellow of the Helen Hay Whitney Foundation. R.A.L. is supported by the UCSF Medical Scientist Training Program, Neuroscience Graduate Program, and Discovery Fellows Program.
    Introduction Hematopoietic stem cells (HSCs) have the lifelong ability to self-renew and generate each of the blood lineages. In vertebrates, definitive hematopoiesis begins with de novo birth of HSCs from hemogenic endothelium along the ventral wall of the dorsal aorta in a conserved region known as the aorta-gonad-mesonephros (AGM) (Dzierzak and Medvinsky, 2008). Studies in zebrafish and mammals have demonstrated that formation of the hematovascular niche is dependent on a signaling cascade between the Hedgehog (Hh) and the Notch pathways. This signaling controls placement of the stem cell leukemia (SCL) transcription factor and induction of the first definitive HSC marker, Runx1 (Gering and Patient, 2005; Kim et al., 2013; Lawson et al., 2002). Based on the conserved role of runx1 in zebrafish (Burns et al., 2005; Kissa and Herbomel, 2010; North et al., 2002), we previously performed a chemical screen to identify regulators of HSC production (North et al., 2007). We recently showed cholesterol-derived estrogens have a crucial role in establishing hemogenic endothelium boundaries (Carroll et al., 2014); the cholesterol derivative vitamin D was likewise identified as a candidate hematopoietic stem and progenitor cell (HSPC) regulator in the screen. Vitamin D synthesis begins with the transformation of 7-dehydrocholesterol in the skin by UV radiation to generate the non-active vitamin D precursor cholecalciferol (D3). Some vertebrates, including teleosts (e.g., zebrafish), obtain D3 primarily from their diet (Lock et al., 2010). D3 is modified by the cytochrome P450 enzyme 2R1 (CYP2R1) to generate 25-hydroxy vitamin D (25(OH)D3), the circulating form of vitamin D, which is then further hydroxylated by CYP27B1 to generate the active vitamin D metabolite, 1,25-dihydroxy vitamin D3 (1,25(OH)D3). Active 1,25(OH)D3 functions as the ligand for the vitamin D receptor (VDR), a member of the nuclear hormone receptor family, resulting in nuclear localization and transcriptional regulation (Plum and DeLuca, 2010). Ligand binding also induces non-genomic cellular responses, including calcium uptake (Norman, 2006). Zebrafish exhibit strong conservation of the vitamin D biosynthetic pathway and its downstream signaling cascade (Craig et al., 2008; Lin et al., 2012).