Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Resource
  • Published:

A genomic atlas of mouse hypothalamic development

Nature Neuroscience volume 13, pages 767–775 (2010)Cite this article

Subjects

Abstract

The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Microarray-based identification of developmentally dynamic transcripts in mouse hypothalamus.
Figure 2: Marker genes that delineate the telencephalic-diencephalic border.
Figure 3: Regional patterning of prethalamus and anterior hypothalamus is revealed by analysis of marker gene expression.
Figure 4: Characterization of molecular markers of regional identity in posteroventral hypothalamus.
Figure 5: Lhx family members delineate discrete regions of the developing hypothalamus.
Figure 6: Diencephalic phenotype of Nkx2.1-Cre × ShhloxP/loxP mice at E10.5 and E12.5, as indicated by analysis of region-specific marker genes.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Mouse Genome Informatics

References

  1. O'Rahilly, S. Human genetics illuminates the paths to metabolic disease. Nature 462, 307–314 (2009).

    Article  CAS  Google Scholar 

  2. Caqueret, A., Yang, C., Duplan, S., Boucher, F. & Michaud, J.L. Looking for trouble: a search for developmental defects of the hypothalamus. Horm. Res. 64, 222–230 (2005).

    CAS  PubMed  Google Scholar 

  3. Fyffe, S.L. et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression and the response to stress. Neuron 59, 947–958 (2008).

    Article  CAS  Google Scholar 

  4. McGill, B.E. et al. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA 103, 18267–18272 (2006).

    Article  CAS  Google Scholar 

  5. Lee, J.E., Wu, S.F., Goering, L.M. & Dorsky, R.I. Canonical Wnt signaling through Lef1 is required for hypothalamic neurogenesis. Development 133, 4451–4461 (2006).

    Article  CAS  Google Scholar 

  6. Dale, J.K. et al. Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 90, 257–269 (1997).

    Article  CAS  Google Scholar 

  7. Manning, L. et al. Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation. Dev. Cell 11, 873–885 (2006).

    Article  CAS  Google Scholar 

  8. Ohyama, K., Das, R. & Placzek, M. Temporal progression of hypothalamic patterning by a dual action of BMP. Development 135, 3325–3331 (2008).

    Article  CAS  Google Scholar 

  9. Shimada, M. & Nakamura, T. Time of neuron origin in mouse hypothalamic nuclei. Exp. Neurol. 41, 163–173 (1973).

    Article  CAS  Google Scholar 

  10. Michaud, J.L., Rosenquist, T., May, N.R. & Fan, C.M. Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev. 12, 3264–3275 (1998).

    Article  CAS  Google Scholar 

  11. Schonemann, M.D. et al. Development and survival of the endocrine hypothalamus and posterior pituitary gland requires the neuronal POU domain factor Brn-2. Genes Dev. 9, 3122–3135 (1995).

    Article  CAS  Google Scholar 

  12. Labosky, P.A. et al. The winged helix gene, Mf3, is required for normal development of the diencephalon and midbrain, postnatal growth and the milk-ejection reflex. Development 124, 1263–1274 (1997).

    CAS  PubMed  Google Scholar 

  13. Wehr, R., Mansouri, A., de Maeyer, T. & Gruss, P. Fkh5-deficient mice show dysgenesis in the caudal midbrain and hypothalamic mammillary body. Development 124, 4447–4456 (1997).

    CAS  PubMed  Google Scholar 

  14. Davis, A.M. et al. Loss of steroidogenic factor 1 alters cellular topography in the mouse ventromedial nucleus of the hypothalamus. J. Neurobiol. 60, 424–436 (2004).

    Article  CAS  Google Scholar 

  15. Acampora, D. et al. Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene. Genes Dev. 13, 2787–2800 (1999).

    Article  CAS  Google Scholar 

  16. Goshu, E. et al. Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus. Mol. Endocrinol. 18, 1251–1262 (2004).

    Article  CAS  Google Scholar 

  17. Gray, P.A. et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306, 2255–2257 (2004).

    Article  CAS  Google Scholar 

  18. Alvarez-Bolado, G. & Eichele, G. Analysing the developing brain transcriptome with the GenePaint platform. J. Physiol. (Lond.) 575, 347–352 (2006).

    Article  CAS  Google Scholar 

  19. Elmquist, J.K., Elias, C.F. & Saper, C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).

    Article  CAS  Google Scholar 

  20. Charlton, H. Hypothalamic control of anterior pituitary function: a history. J. Neuroendocrinol. 20, 641–646 (2008).

    Article  CAS  Google Scholar 

  21. Kruk, M.R. et al. The hypothalamus: cross-roads of endocrine and behavioural regulation in grooming and aggression. Neurosci. Biobehav. Rev. 23, 163–177 (1998).

    Article  CAS  Google Scholar 

  22. Saper, C.B., Scammell, T.E. & Lu, J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 (2005).

    Article  CAS  Google Scholar 

  23. Ulrich-Lai, Y.M. & Herman, J.P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397–409 (2009).

    Article  CAS  Google Scholar 

  24. Büdefeld, T., Grgurevic, N., Tobet, S.A. & Majdic, G. Sex differences in brain developing in the presence or absence of gonads. Dev. Neurobiol. 68, 981–995 (2008).

    Article  Google Scholar 

  25. Tobet, S. et al. Brain sex differences and hormone influences: a moving experience? J. Neuroendocrinol. 21, 387–392 (2009).

    Article  CAS  Google Scholar 

  26. Brown, A.E., Mani, S. & Tobet, S.A. The preoptic area/anterior hypothalamus of different strains of mice: sex differences and development. Brain Res. Dev. Brain Res. 115, 171–182 (1999).

    Article  CAS  Google Scholar 

  27. Peinado, J.R. et al. Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes. Endocrinology 146, 3438–3444 (2005).

    Article  CAS  Google Scholar 

  28. Rinn, J.L. & Snyder, M. Sexual dimorphism in mammalian gene expression. Trends Genet. 21, 298–305 (2005).

    Article  CAS  Google Scholar 

  29. Blackshaw, S. et al. Genomic analysis of mouse retinal development. PLoS Biol. 2, e247 (2004).

    Article  Google Scholar 

  30. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  Google Scholar 

  31. Kiecker, C. & Lumsden, A. Hedgehog signaling from the ZLI regulates diencephalic regional identity. Nat. Neurosci. 7, 1242–1249 (2004).

    Article  CAS  Google Scholar 

  32. Kataoka, A. & Shimogori, T. Fgf8 controls regional identity in the developing thalamus. Development 135, 2873–2881 (2008).

    Article  CAS  Google Scholar 

  33. Grove, E.A., Tole, S., Limon, J., Yip, L. & Ragsdale, C.W. The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development 125, 2315–2325 (1998).

    CAS  PubMed  Google Scholar 

  34. Herrera, E. et al. Foxd1 is required for proper formation of the optic chiasm. Development 131, 5727–5739 (2004).

    Article  CAS  Google Scholar 

  35. Hatini, V., Tao, W. & Lai, E. Expression of winged helix genes, BF-1 and BF-2, define adjacent domains within the developing forebrain and retina. J. Neurobiol. 25, 1293–1309 (1994).

    Article  CAS  Google Scholar 

  36. Pera, E.M. & Kessel, M. Demarcation of ventral territories by the homeobox gene NKX2.1 during early chick development. Dev. Genes Evol. 208, 168–171 (1998).

    Article  CAS  Google Scholar 

  37. Miura, H., Yanazawa, M., Kato, K. & Kitamura, K. Expression of a novel aristaless related homeobox gene Arx in the vertebrate telencephalon, diencephalon and floor plate. Mech. Dev. 65, 99–109 (1997).

    Article  CAS  Google Scholar 

  38. Watson, S.J., Barchas, J.D. & Li, C.H. beta-Lipotropin: localization of cells and axons in rat brain by immunocytochemistry. Proc. Natl. Acad. Sci. USA 74, 5155–5158 (1977).

    Article  CAS  Google Scholar 

  39. Ino, H. Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system. J. Histochem. Cytochem. 52, 311–323 (2004).

    Article  CAS  Google Scholar 

  40. Moga, M.M. & Moore, R.Y. Organization of neural inputs to the suprachiasmatic nucleus in the rat. J. Comp. Neurol. 389, 508–534 (1997).

    Article  CAS  Google Scholar 

  41. Fuller, P.M., Lu, J. & Saper, C.B. Differential rescue of light- and food-entrainable circadian rhythms. Science 320, 1074–1077 (2008).

    Article  CAS  Google Scholar 

  42. Szabó, N.E. et al. Role of neuroepithelial Sonic hedgehog in hypothalamic patterning. J. Neurosci. 29, 6989–7002 (2009).

    Article  Google Scholar 

  43. Dassule, H.R., Lewis, P., Bei, M., Maas, R. & McMahon, A.P. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 127, 4775–4785 (2000).

    CAS  PubMed  Google Scholar 

  44. Xu, Q., Tam, M. & Anderson, S.A. Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506, 16–29 (2008).

    Article  CAS  Google Scholar 

  45. Scholpp, S., Wolf, O., Brand, M. & Lumsden, A. Hedgehog signaling from the zona limitans intrathalamica orchestrates patterning of the zebrafish diencephalon. Development 133, 855–864 (2006).

    Article  CAS  Google Scholar 

  46. Szabó, N.E., Zhao, T., Zhou, X. & Alvarez-Bolado, G. The role of Sonic hedgehog of neural origin in thalamic differentiation in the mouse. J. Neurosci. 29, 2453–2466 (2009).

    Article  Google Scholar 

  47. Mathieu, J., Barth, A., Rosa, F.M., Wilson, S.W. & Peyrieras, N. Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development. Development 129, 3055–3065 (2002).

    CAS  PubMed  Google Scholar 

  48. Tobet, S.A., Paredes, R.G., Chickering, T.W. & Baum, M.J. Telencephalic and diencephalic origin of radial glial processes in the developing preoptic area/anterior hypothalamus. J. Neurobiol. 26, 75–86 (1995).

    Article  CAS  Google Scholar 

  49. Porteus, M.H. et al. DLX-2, MASH-1, and MAP-2 expression and bromodeoxyuridine incorporation define molecularly distinct cell populations in the embryonic mouse forebrain. J. Neurosci. 14, 6370–6383 (1994).

    Article  CAS  Google Scholar 

  50. Hochberg, Y. & Benjamini, Y. More powerful procedures for multiple significance testing. Stat. Med. 9, 811–818 (1990).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank C.-M. Fan for guidance concerning dissection of embryonic hypothalamus and S. Hattar, A. Moore and B. Nelson for comments on the manuscript. This work was supported by the RIKEN Brain Science Institute and Human Frontier Science Project (T.S.), a National Science Foundation Predoctoral Fellowship (D.A.L.), a Basil O'Connor Starter Scholar Award from the March of Dimes (S.B.) and an award from the Klingenstein Fund (S.B.). S.B. is a W.M. Keck Distinguished Young Investigator in Medical Science.

Author information

Author notes

  1. Marina Avetisyan & Lixin Qi

    Present address: Present addresses: Medical Scientist Training Program, Washington University School of Medicine, St. Louis, Missouri, USA (M.A.), University of Illinois School of Medicine, Chicago, Illinois, USA (L.Q.).,

Authors and Affiliations

  1. RIKEN-BSI, 2-1 Hirosawa, Wako-shi, Saitama, Japan.,

    Tomomi Shimogori, Aya C Yoshida, Ayane Kataoka & Hiromi Mashiko

  2. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Daniel A Lee, Ana Miranda-Angulo, Hong Wang, Lizhi Jiang, Marina Avetisyan, Lixin Qi & Seth Blackshaw

  3. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Yanqin Yang, Jiang Qian & Seth Blackshaw

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Seth Blackshaw

  5. Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Seth Blackshaw

  6. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Seth Blackshaw

Authors
  1. Tomomi Shimogori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel A Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Miranda-Angulo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanqin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lizhi Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aya C Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ayane Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiromi Mashiko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marina Avetisyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lixin Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jiang Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Seth Blackshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.B. conceived the study. L.Q. and L.J. dissected tissue, purified RNA and conducted microarray analysis. Y.Y. and J.Q. analyzed microarray data. D.A.L., A.M.-A., L.J., H.W. and M.A. carried out first-pass single-color ISH analysis. A.K., A.C.Y., H.M., L.J. and H.W. carried out the two-color ISH analysis. T.S. and S.B. contributed to the experimental design, supervised experiments, discussed the results and wrote the paper.

Corresponding authors

Correspondence to Tomomi Shimogori or Seth Blackshaw.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 5712 kb)

Supplementary Table 1

Normalized log(2) signal intensity is shown for all probe sets and all microarray samples examined in this study (XLS 29443 kb)

Supplementary Table 2

Median log(2) signal intensity is shown for all 25,471 probe sets that showed significantly different expression (P< 0.01 via one-way ANOVA analysis) at one or more time points when compared to median intensity for that probe set across all time points analyzed. (XLS 7210 kb)

Supplementary Table 3

Summary of all first-pass single color ISH data. (XLS 267 kb)

Supplementary Table 4

Summary of all two-color ISH data. (XLS 260 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shimogori, T., Lee, D., Miranda-Angulo, A. et al. A genomic atlas of mouse hypothalamic development. Nat Neurosci 13, 767–775 (2010). https://doi.org/10.1038/nn.2545

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2545

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing