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The Hyp (hypophosphatemic) mouse, a murine homologue of X-linked hypophosphatemia (XLH) in man, is a Mendelian disorder of phosphate (Pi) homeostasis. The mutant genotype is characterized by abnormal Pi transport at the brush border membrane (BBM) of the proximal tubule and a defect in renal metabolism of vitamin D$ sb3$. The exact nature of these defects has not been elucidated. / In order to determine if the defect is intrinsic to the renal cell or dependent upon an extrinsic humoral factor, I established primary cultures of renal epithelial cells from normal and Hyp mouse kidney. The cultures demonstrated several differentiated properties of epithelial cells of the renal proximal tubule, the site of the Pi transport defect in the Hyp mouse. / Primary cultures initiated from Hyp mice had decreased Pi transport (expressed as an uptake ratio, Pi/$ alpha$-MG), and increased production of 24,25 dihydroxyvitamin D$ sb3$. These results provide evidence for the intrinsic nature of the primary defect in the Hyp mouse. / This appears to be the first time that expression of a mutant transport gene has been demonstrated in cultured renal cells.

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Early identification of mutant embryos prior to the manifestation of a defect facilitates the study of dysmorphogenesis. The In(l)lRk inversion was used as a cytogenetic marker to distinguish embryonic day 9 (D9) splotch (Sp) and splotch-delayed $(Sp sp{d})$ mouse mutants from heterozygous and wild-type littermates, and cellular aspects of abnormal neurulation and NCC migration were examined before inherent neural tube defects (NTDs) and deficiencies in neural crest cell (NCC) derivatives developed. In vitro analysis of NCC emigration from D9 neural tube explants revealed a delay in the release of NCCs from mutant neural tubes compared to controls, suggesting that the primary effect of the mutation was intrinsic to the neuroepithelium. Immunofluorescent localization of the neural cell adhesion molecule (N-CAM) antibody in situ demonstrated an increased intensity of antibody fluorescence in mutant tissue compared to controls, and further characterization by immunoblot analysis showed an altered embryonic N-CAM profile in both Sp and $Sp sp{d}$ mutants at D9 of gestation. The importance of N-CAMs in mediating cellular organization and communication has been well documented, supporting the idea that an alteration in this adhesion mechanism could result in the types of defects seen in splotch locus mouse mutants.

Cell adhesion molecules are known to play crucial roles in a variety of developmental processes. The neural cell adhesion molecule N-CAM is strongly implicated in neurulation and neural crest cell (NCC) migration and was thus studied in splotch (Sp) neural tube defect mutant embryos. At the 20 somite-stage of gestation day 9, Sp N-CAM was found to contain polysialic acid (PSA) side chains which are normally only present beginning at gestational day 11. Younger embryos at 12 and 14 somites also showed the presence of PSA on N-CAM, which was absent in controls. Enzymatic removal of PSA from N-CAM resulted in isoforms which migrated identically to PSA-free N-CAM isoforms in SDS-polyacrylamide gels. The post-translational modification of N-CAM appears to be the primary target of the Sp gene. In view of N-CAM's importance during development, an alteration at a critical stage is likely to result in the cascade of abnormalities seen in Sp mutants. / A new genotyping assay was also implemented for examination of N-CAM in Sp and other related wildtype strains.

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