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Rnx deficiency results in congenital central hypoventilation

Nature Genetics volume 24, pages 287–290 (2000)Cite this article

Abstract

The genes Tlx1 (Hox11), Enx (Hox11L1, Tlx-2 ) and Rnx (Hox11L2, Tlx-3) constitute a family of orphan homeobox genes1,2,3,4,5,6,7,8,9,10. In situ hybridization has revealed considerable overlap in their expression within the nervous system, but Rnx is singularly expressed in the developing dorsal and ventral region of the medulla oblongata. Tlx1-deficient and Enx-deficient mice display phenotypes in tissues where the mutated gene is singularly expressed, resulting in asplenogenesis3,4 and hyperganglionic megacolon8, respectively. To determine the developmental role of Rnx, we disrupted the locus in mouse embryonic stem (ES) cells. Rnx-deficient mice developed to term, but all died within 24 hours after birth from a central respiratory failure. The electromyographic activity of intercostal muscles coupled with the C4 ventral root activity assessed in a medulla-spinal cord preparation revealed a high respiratory rate with short inspiratory duration and frequent apnea. Furthermore, a coordinate pattern existed between the abnormal activity of inspiratory neurons in the ventrolateral medulla and C4 motorneuron output, indicating a central respiratory defect in Rnx−/− mice. Thus, Rnx is critical for the development of the ventral medullary respiratory centre and its deficiency results in a syndrome resembling congenital central hypoventilation.

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Figure 1: Rnx expression in the developing embryo.
Figure 2: Rnx expression in the developing nervous system.
Figure 3: Generation of Rnx-deficient mice.
Figure 4: Respiratory distress in an Rnx−/− mouse.
Figure 5: Respiratory analysis.

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Acknowledgements

We thank D. Maher and E. Smith for preparation of this manuscript; and K. Ezure for encouragement and discussion. This research was supported in part by Grant-In-Aid for Exploratory Research from Japan Society for the Promotion of Science (to A.A.) and Grant-In-Aid for Scientific Research on Priority Areas (to S.S.).

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Authors and Affiliations

  1. Departments of Medicine and Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis , Missouri, USA

    Senji Shirasawa, Kevin A. Roth, Gary A. Brown, Susan Horning & Stanley J. Korsmeyer

  2. Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Senji Shirasawa, Koji Okumura & Takehiko Sasazuki

  3. Department of Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, 138, Japan

    Akiko Arata

  4. Department of Physiology, Showa University School of Medicine, Tokyo, Japan

    Akiko Arata & Hiroshi Onimaru

  5. Center for Biotechnology, Showa University, Tokyo, Japan

    Satoru Arata

  6. Dana-Farber Cancer Institute, Harvard Medical School , Massachusetts, Boston, USA

    Stanley J. Korsmeyer

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  1. Senji Shirasawa
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Correspondence to Stanley J. Korsmeyer.

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Shirasawa, S., Arata, A., Onimaru, H. et al. Rnx deficiency results in congenital central hypoventilation. Nat Genet 24, 287–290 (2000). https://doi.org/10.1038/73516

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