title: Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures.
abstract: In most cells, the ubiquitously expressed Na+/H+ exchanger isoform 1 (NHE1) is thought to be a primary regulator of pH homeostasis, cell volume regulation, and the proliferative response to growth factor stimulation. To study the function of NHE1 during embryogenesis when these cellular processes are very active, we targeted the Nhe1 gene by replacing the sequence encoding transmembrane domains 6 and 7 with the neomycin resistance gene. NHE activity assays on isolated acinar cells indicated that the targeted allele is functionally null. Although the absence of NHE1 is compatible with embryogenesis, Nhe1 homozygous mutants (-/-) exhibit a decreased rate of postnatal growth that is first evident at 2 wk of age. At this time, Nhe1 -/- animals also begin to exhibit ataxia and epileptic-like seizures. Approximately 67% of the -/- mutants die before weaning. Postmortem examinations frequently revealed an accumulation of a waxy particulate material inside the ears, around the eyes and chin, and on the ventral surface of the paws. Histological analysis of adult tissues revealed a thickening of the lamina propria and a slightly atrophic glandular mucosa in the stomach.
authors: Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati 45229, Ohio. sheila.bell@chmcc.org
authors: S M
authors: SM
authors: Bell
authors: C M
authors: CM
authors: Schreiner
authors: P J
authors: PJ
authors: Schultheis
authors: M L
authors: ML
authors: Miller
authors: R L
authors: RL
authors: Evans
authors: C V
authors: CV
authors: Vorhees
authors: G E
authors: GE
authors: Shull
authors: W J
authors: WJ
authors: Scott
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D001835:Body Weight; D002678:Chimera; D003433:Crosses, Genetic; D003643:Death; D005314:Embryonic and Fetal Development; D005091:Exons; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D006130:Growth Disorders / Q000235:genetics* / Q000503:physiopathology; D006720:Homozygote; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D000584:Amiloride; C039614:ethylisopropylamiloride