TY - JOUR
T1 - Rnx deficiency results in congenital central hypoventilation
AU - Shirasawa, Senji
AU - Arata, Akiko
AU - Onimaru, Hiroshi
AU - Roth, Kevin A.
AU - Brown, Gary A.
AU - Horning, Susan
AU - Arata, Satoru
AU - Okumura, Koji
AU - Sasazuki, Takehiko
AU - Korsmeyer, Stanley J.
N1 - Funding Information:
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.).
PY - 2000/3
Y1 - 2000/3
N2 - The genes Tlx 1 (Hox11), Enx (Hox11L1, Tlx-2) and Rnx (Hox11L2, Tlx-3) constitute a family of orphan homeobox genes. 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 asplenogenesis and hyperganglionic megacolon, 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.
AB - The genes Tlx 1 (Hox11), Enx (Hox11L1, Tlx-2) and Rnx (Hox11L2, Tlx-3) constitute a family of orphan homeobox genes. 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 asplenogenesis and hyperganglionic megacolon, 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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U2 - 10.1038/73516
DO - 10.1038/73516
M3 - Article
C2 - 10700185
AN - SCOPUS:17544388670
VL - 24
SP - 287
EP - 290
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 3
ER -