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A genomic atlas of mouse hypothalamic development

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

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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.

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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.

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Gene Expression Omnibus

Mouse Genome Informatics

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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

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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.

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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)

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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

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