Rnx deficiency results in congenital central hypoventilation

Abstract

The genes Tlx1 (Hox11), Enx (Hox11L2, 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.

Absence ofNdn, Encoding the Prader-Willi Syndrome-Deleted Genenecdin, Results in Congenital Deficiency of Central Respiratory Drive in Neonatal Mice

“…Thus, absence of necdin expression could result in the loss, or perturbation of function, of rhythmogenic neurons in the pre-Bötzinger complex. This is the proposed abnormality in Rnx-deficient mice, which also have a central respiratory defect, possibly attributable to altered cell-fate commitment of respiratory neurons attributable to loss of this homeobox transcription factor (Shirasawa et al, 2000;Qian et al, 2001). Alternatively, necdin expression may be necessary for the proper functioning of neurons providing appropriate conditioning drive impinging on rhythmogenic neurons within the preBötzinger complex.…”

Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1

“…To determine the roles of Rnx and Tlx-1 during development of D4 interneurons, we analyzed Rnx and Tlx-1 single or double mutants (Roberts et al 1994;Shirasawa et al 2000). In the medulla of E11.5 Rnx/Tlx-1 double mutants, expression of both Lmx1b and Phox2a is eliminated in the lateral area (Fig.…”

“…Cold Spring Harbor Laboratory Press on May 10, 2018 -Published by genesdev.cshlp.org Downloaded from (Shirasawa et al 2000). Here we demonstrate that Rnx and Tlx-1 together are also required for proper development of most relay somatic sensory neurons, including the spinal-trigeminal nucleus (Sp5), the dorsal horn of the spinal cord, and a portion of the principle trigeminal nucleus (Pr5).…”

“…The origin of Drg11-positive neurons and the fates of Mash1-positive precursors are also poorly understood. The Tlx family of homeobox genes contains three members, Tlx-1/Hox11, Enx/Hox11-L1/Tlx-2, and Rnx/ Hox11L2/Tlx-3 (Dube et al 1991;Hatano et al 1991;Kennedy et al 1991;Dear et al 1993Dear et al , 1995Raju et al 1993;Roberts et al 1994;Hatano et al 1997;Shirasawa et al 1997Shirasawa et al , 2000Logan et al 1998;Tang et al 1998). In the developing hindbrain and spinal cord, Rnx and Tlx-1 are initially expressed in longitudinal columns of cells, extending through the hindbrain and spinal cord ( Fig.…”

The nuclear oncoprotein TLX1/HOX11 associates with pericentromeric satellite 2 DNA in leukemic T-cells

“…[1][2][3][4][5] The first identified member of the family, TLX1, was discovered via chromosomal translocations involving the 10q24 locus specifically occurring in T-cell acute lymphoblastic leukemia (T-ALL). [6][7][8] TLX1 encodes a transcription factor that is essential for spleen development.…”