The mammalian Nell1 gene encodes a protein kinase C-beta1 (PKC-beta1) binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Over-expression of Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of the growing cranial bone fronts. Here, we report the generation, positional cloning and characterization of Nell1(6R), a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea. Nell1(6R) has a T-->A base change that converts a codon for cysteine into a premature stop codon [Cys(502)Ter], resulting in severe truncation of the predicted protein product and marked reduction in steady-state levels of the transcript. In addition to the expected alteration of cranial morphology, Nell1(6R) mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative reverse transcription-PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix (ECM) proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder Ehlers-Danlos Syndrome and other disorders associated with spinal curvature anomalies. Nell1(6R) mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chrondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of ECM proteins can lead to anomalies in these structures.
chromosomes resemble each other closely within synOne of the larger contiguous blocks of mouse-hu-tenic blocks that vary widely in size, containing just man genomic homology includes the proximal portion a few to several hundred related genes (reviewed by of mouse chromosome 7 and the long arm of human Copeland et al., 1993). Within the best-mapped of these chromosome 19. Previous studies have demonstrated syntenically homologous regions, the presence and lothe close relationship between the two regions, but cation of specific genes can be accurately predicted in have also indicated significant rearrangements in the one species, based upon the mapping results obtained relative orders of homologous mouse and human in the other. In many cases, information regarding gene genes. Here we present the genetic locations of the function derived from the analysis of human hereditary homologs of 42 human chromosome 19q markers in the traits or mapped murine mutations may also be extrapmouse, with an emphasis on genes also included in olated from one species to another (e.g., Ton et al., 1992; the human chromosome 19 physical map. Our results Giebel and Spritz, 1991). However, local rearrangedemonstrate that despite an overall inversion of sements, including apparent deletions, inversions, inserquences relative to the centromere, apparent ''transtions, and transposition events, have occurred within positions'' of three gene-rich segments, and a local inthese homologous blocks during the course of evolution, version of markers mapping near the 19q telomere, gene content, order, and spacing are remarkably well so that relationships between syntenically homologous conserved throughout the lengths of these related mouse and human regions are not always as straightmouse and human regions. Although most human 19q forward as they may seem on the grosser level. Consemarkers have remained genetically linked in mouse, quently, the power of prediction afforded in any homolone small human segment forms a separate region of ogy region increases tremendously with the level of reshomology between human chromosome 19q and mouse olution and degree of internal consistency associated chromosome 17. Three of the four rearrangements of with a particular set of comparative mapping data. mouse versus human 19q sequences involve segmentsOne of the larger contiguous blocks of mouse-human that are located directly adjacent to each other in genomic homology includes the proximal portion of portant new tool to aid in the mapping of genes and Cavanna et al., 1990; Brown et al., 1993; reviewed by associated phenotypes in both species. ᭧ 1996 Academic Press, Inc. Brilliant et al., 1994), but have also indicated that a significant amount of rearrangement has occurred between the mouse and the human segments. The recent
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