Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice.
Nurr1, a transcription factor belonging to the family of nuclear receptors, is expressed at high levels immediately after birth. Gene-targeted mice lacking Nurr1 fail to develop midbrain dopaminergic neurones and do not survive beyond 24 h after birth. Dopamine (DA) levels may be regulated by Nurr1, and as DA is involved in both central and peripheral respiratory control, we hypothesized that lack of Nurr1 may impair breathing and cause death by respiratory failure. We demonstrate herein that Nurr1 newborn knockout mice have a severely disturbed breathing pattern characterized by hypoventilation, numerous apnoeas and failure to increase breathing when challenged with hypoxia. In heterozygote Nurr1 mice the response to hypoxia is also altered. Furthermore, the central respiratory rhythm, generated from isolated brainstem-spinal cord preparations, exhibits impaired response to hypoxia in mice lacking Nurr1. Moreover, Nurr1 is expressed in several respiratory-related regions of the nervous system, including the nucleus of the solitary tract, the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve, and in the carotid bodies. The prominent Nurr1 expression in these areas, involved in respiratory control, along with the severe respiratory phenotype, indicates that Nurr1 plays a major role in the extrauterine adaption of respiratory control and the response to hypoxia.
Nsegbe
Elise
E
Karolinska Institutet, Neonatal Unit, Astrid Lindgren Children's Hospital, S-171 76 Stockholm, Sweden.
Wallén-Mackenzie
Asa
A
Dauger
Stephane
S
Roux
Jean-Christophe
JC
Shvarev
Yuri
Y
Lagercrantz
Hugo
H
Perlmann
Thomas
T
Herlenius
Eric
E
D000818:Animals; D000831:Animals, Newborn; D000917:Antibody Formation; D001931:Brain Mapping; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D002344:Carotid Body / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency*; D007040:Hypoventilation / Q000151:congenital* / Q000503:physiopathology*; D000860:Hypoxia / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012119:Respiration; D012125:Respiratory Center / Q000503:physiopathology; D015656:Respiratory Mechanics; D012137:Respiratory System / Q000503:physiopathology; D014157:Transcription Factors / Q000172:deficiency*
D004268:DNA-Binding Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors