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SOX3 is required during the formation of the hypothalamo-pituitary axis

Nature Genetics volume 36, pages 247–255 (2004)Cite this article

Abstract

The pituitary develops from the interaction of the infundibulum, a region of the ventral diencephalon, and Rathke's pouch, a derivative of oral ectoderm. Postnatally, its secretory functions are controlled by hypothalamic neurons, which also derive from the ventral diencephalon. In humans, mutations affecting the X-linked transcription factor SOX3 are associated with hypopituitarism and mental retardation, but nothing is known of their etiology. We find that deletion of Sox3 in mice leads to defects of pituitary function and of specific central nervous system (CNS) midline structures. Cells in the ventral diencephalon, where Sox3 is usually highly expressed, have altered properties in mutant embryos, leading to abnormal development of Rathke's pouch, which does not express the gene. Pituitary and hypothalamic defects persist postnatally, and SOX3 may also function in a subset of hypothalamic neurons. This study shows how sensitive the pituitary is to subtle developmental defects and how one gene can act at several levels in the hypothalamic-pituitary axis.

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Figure 1: Conditional targeted inactivation of Sox3.
Figure 2
Figure 3: Gonadal histology, pituitary hormone levels and growth hormone immunohistochemistry.
Figure 4: Abnormal morphogenesis of the hypothalamus, pituitary and midline CNS structures in Sox3 mutant mice.
Figure 5: Altered domains of expression of Fgf8 and Bmp4 during early development of the pituitary in Sox3 mutants.
Figure 6: GFP expression from Sox3Δgfp in XY hemizygous and XX heterozygous embryos and pituitary defects in heterozygotes.
Figure 7: Proliferation in the infundibulum and hypothalamic region of XX heterozygous Sox3Δgfp embryos.
Figure 8: Histological analysis and GFP immunofluorescence of the hypothalamus in the postnatal brain of Sox3 mutants.

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Acknowledgements

We thank I. Harragan and W. Hatton for assistance with histology, J. Turner and P. Burgoyne for sharing their expertise in gonadal phenotypes, D. Whittcut and P. Mealyer for taking good care of the mouse colony, L. Dubois and J.-P. Vincent for critical reading of the manuscript and C. Wise and other members of the laboratory for their help and encouragement. This work was supported by the MRC, by a European Union Network Grant and the Louis Jeantet Foundation and by Marie Curie Postdoctoral Fellowships to K.R. and S.B.

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Author notes

  1. Silvia Brunelli

    Present address: Stem Cell Research Institute, DIBIT-HSR, via Olgettina 58, 20132, Milan, Italy

  2. Karine Rizzoti and Silvia Brunelli: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Karine Rizzoti, Silvia Brunelli & Robin Lovell-Badge

  2. Division of Molecular Neuroendocrinology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Danielle Carmignac & Iain C Robinson

  3. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia

    Paul Q Thomas

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Correspondence to Robin Lovell-Badge.

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Rizzoti, K., Brunelli, S., Carmignac, D. et al. SOX3 is required during the formation of the hypothalamo-pituitary axis. Nat Genet 36, 247–255 (2004). https://doi.org/10.1038/ng1309

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