Molecular genetics of neurocristopathy

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The Ncx gene which belongs to the Hox11 homeobox family gene specifically expressed in neural crest derived tissues. Ncx/Hox11L.1-deficient (Ncx-KO) mice have a megacolon with an increased number of neuronal cells in the enteric ganglia. (1) Neuronal cell death in enteric ganglia is impaired in Ncx deficient mice resulting in an increased number of neuronal cells. Typical findings of human intestinal neuronal dysplasia (ectopic ganglia, in the mucosal and muscular layers on AchE histochemistry, ghost-like ganglia on NADPH diaphorase histochemistry) were foung in enteric plexus of Ncx deficient mice. (2)Neuronal cells were more numerous in vesical ganglia from Ncx-KO mice than in ganglia from controls. The intraperitoneal injection of an inhibitor of nitric oxide synthase (NOS) increased the threshold pressure and the remaining pressure in cystometrograms from Ncx-KO mice to the control level. The increased number of neuronal cells in vesical ganglia induces dysfunction of vesico-urethral sphincter muscle in Ncx-KO mice. The amount of nitric oxide in vesical nerve cells is important to control function of the vesico-urethral sphincter muscle. (3) During a process of a RDA method using enteric neuron cDNAs from wild type and Ncx-deficient mice, we obtained novel kelch family gene and named Nd1(Ncx downstream gene 1 ). We are characterizing a function of Nd1 in vivo by creating transgenic and knockout mice.