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The LIM Homeodomain Factor Lhx2 Is Required for Hypothalamic Tanycyte Specification and Differentiation

Salvatierra, Juan and Lee, Daniel A. and Zibetti, Cristina and Duran-Moreno, Maria and Yoo, Sooyeon and Newman, Elizabeth A. and Wang, Hong and Bedont, Joseph L. and de Melo, Jimmy and Miranda-Angulo, Ana L. and Gil-Perotin, Sara and Garcia-Verdugo, Jose Manuel and Blackshaw, Seth (2014) The LIM Homeodomain Factor Lhx2 Is Required for Hypothalamic Tanycyte Specification and Differentiation. Journal of Neuroscience, 34 (50). pp. 16809-16820. ISSN 0270-6474. PMCID PMC4261103. https://resolver.caltech.edu/CaltechAUTHORS:20150109-091224685

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Abstract

Hypothalamic tanycytes, a radial glial-like ependymal cell population that expresses numerous genes selectively enriched in embryonic hypothalamic progenitors and adult neural stem cells, have recently been observed to serve as a source of adult-born neurons in the mammalian brain. The genetic mechanisms that regulate the specification and maintenance of tanycyte identity are unknown, but are critical for understanding how these cells can act as adult neural progenitor cells. We observe that LIM (Lin-11, Isl-1, Mec-3)-homeodomain gene Lhx2 is selectively expressed in hypothalamic progenitor cells and tanycytes. To test the function of Lhx2 in tanycyte development, we used an intersectional genetic strategy to conditionally delete Lhx2 in posteroventral hypothalamic neuroepithelium, both embryonically and postnatally. We observed that tanycyte development was severely disrupted when Lhx2 function was ablated during embryonic development. Lhx2-deficient tanycytes lost expression of tanycyte-specific genes, such as Rax, while also displaying ectopic expression of genes specific to cuboid ependymal cells, such as Rarres2. Ultrastructural analysis revealed that mutant tanycytes exhibited a hybrid identity, retaining radial morphology while becoming multiciliated. In contrast, postnatal loss of function of Lhx2 resulted only in loss of expression of tanycyte-specific genes. Using chromatin immunoprecipitation, we further showed that Lhx2 directly regulated expression of Rax, an essential homeodomain factor for tanycyte development. This study identifies Lhx2 as a key intrinsic regulator of tanycyte differentiation, sustaining Rax-dependent activation of tanycyte-specific genes while also inhibiting expression of ependymal cell-specific genes. These findings provide key insights into the transcriptional regulatory network specifying this still poorly characterized cell type.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.1711-14.2014DOIArticle
http://www.jneurosci.org/content/34/50/16809PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261103/PubMed CentralArticle
ORCID:
AuthorORCID
Lee, Daniel A.0000-0001-7411-2740
Garcia-Verdugo, Jose Manuel0000-0001-9872-6499
Additional Information:© 2014 the authors. Beginning six months after publication SfN’s license will be nonexclusive and SfN grants the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license. Received April 2, 2014; revised Oct. 24, 2014; accepted Oct. 29, 2014. This work was supported by National Institutes of Health Grants R01EY020560 and R21NS067393. S.B. was a W.M. Keck Distinguished Young Scholar in Medical Research. M.D.-M. holds a predoctoral fellowship from the Spanish government (AP2009-4759) and S.G.-P. holds a postdoctoral fellowship (CM12/00014) from the Health Institute Carlos III. D.A.L. is a Ruth L. Kirschstein Postdoctoral Fellow (National Institutes of Health National Research Service Award F32 NS084769). We thank W. Yap, S. Aja, and members of the Blackshaw laboratory for comments on the manuscript. The authors declare no competing financial interests. J.S. and D.A.L. contributed equally to this work. Author contributions: J.S., D.A.L., and S.B. designed research; J.S., D.A.L., C.Z., M.D.-M., S.Y., E.A.N., H.W., J.L.B., J.d.M., and S.B. performed research; A.L.M.-A. contributed unpublished reagents/analytic tools; J.S., D.A.L., C.Z., M.D.-M., S.Y., E.A.N., J.L.B., S.G.-P., J.M.G.-V., and S.B. analyzed data; J.S., D.A.L., and S.B. wrote the paper.
Funders:
Funding AgencyGrant Number
NIHR01EY020560
NIHR21NS067393
Spanish governmentAP2009-4759
Health Institute Carlos IIICM12/00014
NIHF32 NS084769
W. M. Keck FoundationUNSPECIFIED
Subject Keywords:transcription factor; hypothalamus; metabolism; ependymal cells; radial glia; tanycytes
Issue or Number:50
PubMed Central ID:PMC4261103
Record Number:CaltechAUTHORS:20150109-091224685
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150109-091224685
Official Citation:Salvatierra, J., Lee, D. A., Zibetti, C., Duran-Moreno, M., Yoo, S., Newman, E. A., . . . Blackshaw, S. (2014). The LIM Homeodomain Factor Lhx2 Is Required for Hypothalamic Tanycyte Specification and Differentiation. The Journal of Neuroscience, 34(50), 16809-16820. doi: 10.1523/jneurosci.1711-14.2014
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53458
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:09 Jan 2015 18:14
Last Modified:09 Mar 2020 13:18

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