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Tanycytes of the Adult Hypothalamic Third Ventricle Include Distinct Populations of FGF-Responsive Neural Progenitors

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Tanycytes of the Adult Hypothalamic Third Ventricle Include Distinct Populations of FGF-Responsive Neural Progenitors ARTICLE Received 27 Nov 2012 | Accepted 23 May 2013 | Published 27 Jun 2013 DOI: 10.1038/ncomms3049 OPEN a-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors S.C. Robins1,2,*, I. Stewart1,*, D.E McNay3,4,*, V. Taylor5, C. Giachino5, M. Goetz6, J. Ninkovic6, N. Briancon3,7, E. Maratos-Flier3, J.S Flier3,8, M.V Kokoeva2,3 & M. Placzek1 Emerging evidence suggests that new cells, including neurons, can be generated within the adult hypothalamus, suggesting the existence of a local neural stem/progenitor cell niche. Here, we identify a-tanycytes as key components of a hypothalamic niche in the adult mouse. Long-term lineage tracing in vivo using a GLAST::CreERT2 conditional driver indicates that a-tanycytes are self-renewing cells that constitutively give rise to new tanycytes, astrocytes and sparse numbers of neurons. In vitro studies demonstrate that a-tanycytes, but not b-tanycytes or parenchymal cells, are neurospherogenic. Distinct subpopulations of a-tanycytes exist, amongst which only GFAP-positive dorsal a2-tanycytes possess stem-like neurospherogenic activity. Fgf-10 and Fgf-18 are expressed specifically within ventral tanycyte subpopulations; a-tanycytes require fibroblast growth factor signalling to maintain their proliferation ex vivo and elevated fibroblast growth factor levels lead to enhanced proliferation of a-tanycytes in vivo. Our results suggest that a-tanycytes form the critical component of a hypothalamic stem cell niche, and that local fibroblast growth factor signalling governs their proliferation. 1 MRC Centre for Developmental and Biomedical Genetics and Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. 2 Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada H3A 1A1. 3 Beth Israel Deaconess Medical Centre, Division of Endocrinology, Diabetes and Metabolism, Centre for Life Sciences, Boston, Massachusetts 02215, USA. 4 Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB392PN, UK. 5 Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland. 6 Institute for Stem Cell Research, Helmholtz Center, Munich, Germany. 7 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. 8 Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to M.P. (email: m.placzek@sheffield.ac.uk). NATURE COMMUNICATIONS | 4:2049 | DOI: 10.1038/ncomms3049 | www.nature.com/naturecommunications 1 & 2013 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3049 dult neural stem cell niches, harbouring neural stem and migration route for newborn cells. However, the sparse numbers progenitor cells and supporting adult neurogenesis, have of neurons that we observe suggests that a-tanycytes are not Abeen well described in the subventricular zone (SVZ) of overtly neurogenic in the unchallenged adult mouse. We show, the lateral ventricles and the subgranular zone (SGZ) of the further, that defined tanycyte subpopulations have different hippocampal dentate gyrus. In addition, in vivo analyses show neural precursor characteristics: GLAST À ive b-tanycytes are constitutive proliferation, neurogenesis and astrocyte generation unable to form neurospheres, while GLAST þ ive a-tanycytes are within a third region of the adult brain, the hypothalamus1–5. neurosphere-forming. Of these, only the dorsal a2 subset have the Here, neurogenesis and gliogenesis can be attenuated through the unlimited self-renewal capacity of stem cells; other subsets appear manipulation of secreted trophic factors, de novo neurogenesis, in to represent progenitors with a more limited self-renewal particular, associated with energy balance1,2,4,6,7. capacity. Finally, through infusion of fibroblast growth factor The precise location, identity and potential of adult hypotha- (FGF)-2 in vivo and inhibition of FGF signalling ex vivo,we lamic stem/progenitor cell(s), however, remain unclear. Within demonstrate that FGF signalling is necessary and sufficient for the adult hypothalamus, cells around the third ventricle form a-tanycyte proliferation. Our study raises the intriguing possibility neurospheres (a hallmark of neural stem cells (NSCs)8–10). that local FGF signalling governs cellular homeostasis within a These studies have raised the possibility that the adult hypothalamic stem cell niche. hypothalamus contains NSCs in a niche near the third ventricle. However, tanycytes, ependymocytes, subventricular Results astrocytes and parenchymal glial cells all reside near the third Distinct tanycyte subpopulations line the third ventricle.We ventricle, and each is a potential adult stem and progenitor cell first confirmed the location of hypothalamic tanycytes, examining candidate2,5–8,11–13. expression of the intermediate filament marker, Vimentin. Hypothalamic tanycytes resemble embryonic radial glia, with a Expression is restricted to tanycytes (Fig. 1a) in the central/pos- cell body at the ventricular zone and a long basally extending terior hypothalamus (Supplementary Fig. S1a) and reveals their process, their morphology well-suited to their postulated role as cardinal morphological features: a cell body located in the ven- modulators of neuroendocrine activity and homeostasis (reviewed 13–16 tricular lining, and a long basally projecting process (Fig. 1a, in ). Within the hypothalamus, tanycyte cell bodies are right-hand panels) that distinguishes them from ependymocytes. strictly localised to the central and posterior hypothalamus (level The position and projection of the Vimentin þ ive process defines of the median eminence and premammillary nucleus, classic tanycyte subsets: b-tanycytes line the median eminence; respectively). Here they constitute the main cell type lining the a2-tanycytes reside adjacent to the arcuate nucleus; a1-tanycytes ventral third of the third ventricle, interdigitating with ciliated extend from the level of the ventromedial nucleus to the dorso- ependymal cells that lack a basal process (ependymocytes) more 25,26 17–21 medial nucleus (Fig. 1) . Tanycytes express proteins associated dorsally . Morphological studies have mapped and defined with NSCs in other brain regions: all tanycytes appear to co- subpopulations of tanycytes according to their position and express Vimentin and Nestin (Fig. 1b) and many appear to b process projection. Ventral-most -tanycytes line the express SOXB1 proteins (Supplementary Fig. S1a,b)7. infundibulum and median eminence, while adjacent a-tanycytes Double-label analyses with Nestin shows expression of GFAP in line regions of the ventricular zone (VZ) that are adjacent to tanycytes lining the third ventricle (Fig. 1c). However, in contrast hypothalamic nuclei and project laterally, contacting capillaries to Vimentin/Nestin, GFAP is restricted to particular tanycyte and neurons of the arcuate and ventromedial nuclei en 14,18,19 subsets. Expression is detected, in particular, on dorsal a2-tanycytes passant . (da2) and some a1-tanycytes (Fig. 1c,d green and purple Increasing numbers of studies have focused attention on arrowheads, respectively). Little/no GFAP expression is detected tanycytes as potential adult NSCs. In the adult rat, fate-mapping on ventral-most a2-tanycytes (va2) or b-tanycytes (Fig. 1c,d blue experiments of the hypothalamic ventricular wall first showed and red arrowheads, respectively). Thus, GFAP expression that proliferating ependymal cells, including but not exclusively distinguishes da2-tanycytes from va2- and b-tanycytes. tanycytes, can give rise to progeny that migrate along tanycyte 11 Together, these observations confirm previous studies showing processes . Additional studies in the adult rat revealed an that tanycytes occupy the ventricular lining of the hypothalamus, enhanced proliferation of tanycytes in response to IGF-16. In the confirm that tanycytes express markers indicative of neural stem/ mouse, lineage-tracing studies have demonstrated that a subset of progenitor cells and reveal the presence of different tanycyte b-tanycytes, the b2-tanycytes, can proliferate and are neurogenic, subsets. contributing new neurons to hypothalamic nuclei in the postnatal/juvenile period22. Furthermore, a recent comple- mentary study suggests that ventrally located tanycytes, including GLAST::CreERT2 labels a-tanycytes.Althoughrecentstudies b-tanycytes, can proliferate in early adulthood, giving rise to new have focused attention on b2-tanycytes as proliferating progeni- neurons23. However, in contrast to the SVZ of the lateral ventricle tors22,23, earlier studies suggested that a-tanycytes may harbour wall24, lineage-tracing studies have not yet identified a self- neural stem/progenitor potential in the adult6,11.Toexamine renewing multipotent neural stem-like cell in the adult. It remains whether adult a-tanycytes possess neural stem/progenitor unclear, moreover, if adult tanycytes have stem-like or functions, we searched for an appropriate genetic means to label progenitor-like activity; indeed it is unknown if adult tanycytes them. Adult GLAST::CreERT2 mice27,28 were crossed with Cre are homogeneous in terms of their neural precursor status. These reporter mice that ubiquitously express either b-gal or GFP (z/EG questions, and the question of the extent of activity of adult mice) following
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