Rnx deficiency results in congenital central hypoventilation

The genes Tlx1 (Hox11), Enx (Hox11L1, Tlx-2) and Rnx (Hox11L2, Tlx-3) const itute a family of orphan homeobox genes(1-10). In situ hybridization has re vealed 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 ph enotypes in tissues where the mutated gene is singularly expressed, resulti ng in asplenogenesis(3,4) and hyperganglionic megacolon(8), respectively. T o determine the developmental role of Rnx. we disrupted the locus in mouse embryonic stem (ES) cells. Rnx-deficient mice developed to term, but all di ed within 24 hours after birth from a central respiratory failure. The elec tromyographic activity of intercostal muscles coupled with the C4 ventral r oot activity assessed in a medulla-spinal cord preparation revealed a high respiratory rate with short inspiratory duration and frequent apnea. Furthe rmore, a coordinate pattern existed between the abnormal activity of inspir atory neurons in the ventrolateral medulla and C4 motorneuron output, indic ating a central respiratory defect in Rnx(-/-) mice. Thus, Rnx is critical for the development of the ventral medullary respiratory centre and its def iciency results in a syndrome resembling congenital central hypoventilation .