Discs-large homolog 1 (DLGH1) is a mouse ortholog of the Drosophila discs-large (DLG) tumor suppressor protein, a founding member of the PDZ and MAGUK protein families. DLG proteins play important roles in regulating cell proliferation, epithelial cell polarity, and synapse formation and function. Here, we generated a null allele of Dlgh1 and studied its role in urogenital development. Dlgh1 ؊/؊ mice developed severe urinary tract abnormalities, including congenital hydronephrosis, which is the leading cause of renal failure in infants and children. DLGH1 is expressed in the developing ureter; in its absence, the stromal cells that normally lie between the urothelial and smooth muscle layers were missing. Moreover, in ureteric smooth muscle, the circular smooth muscle cells were misaligned in a longitudinal orientation. These abnormalities in the ureter led to severely impaired ureteric peristalsis. Similar smooth muscle defects are observed frequently in patients with ureteropelvic junction obstruction, a common form of hydronephrosis. Our results suggest that (i) besides its well documented role in regulating epithelial polarity, Dlgh1 also regulates smooth muscle orientation, and (ii) human DLG1 mutations may contribute to hereditary forms of hydronephrosis.SAP97 ͉ kidney ͉ postsynaptic density-95/discs-large/zonula occludens-1 ͉ urogenital ͉ sonic hedgehog

Integrin receptors for the extracellular matrix and receptor tyrosine kinase growth factor receptors represent two of the major families of receptors that transduce into cells information about the surrounding environment. Wnt proteins are a major family of signaling molecules that regulate morphogenetic events. There is presently little understanding of how the expression of Wnt genes themselves is regulated. In this study, we demonstrate that α3β1 integrin, a major laminin receptor involved in the development of the kidney, and c-Met, the receptor for hepatocyte growth factor, signal coordinately to regulate the expression of Wnt7b in the mouse. Wnt signals in turn appear to regulate epithelial cell survival in the papilla of the developing kidney, allowing for the elongation of epithelial tubules to form a mature papilla. Together, these results demonstrate how signals from integrins and growth factor receptors can be integrated to regulate the expression of an important family of signaling molecules so as to regulate morphogenetic events.

Individuals with congenital renal hypoplasia display a defect in the growth of nephrons during development. Many genes that affect the initial induction of nephrons have been identified, but little is known about the regulation of postinductive stages of kidney development. In the absence of the growth factor bone morphogenic protein 7 (BMP7), kidney development arrests after induction of a small number of nephrons. The role of BMP7 after induction, however, has not been fully investigated. Here, we generated a podocyte-specific conditional knockout of BMP7 (Bmp7 flox/flox ;Nphs2-Cre ϩ [BMP7 CKO]) to study the role of podocyte-derived BMP7 in nephron maturation. By postnatal day 4, 65% of BMP7 CKO mice had hypoplastic kidneys, but glomeruli demonstrated normal patterns of laminin and collagen IV subunit expression. Developing proximal tubules, however, were reduced in number and demonstrated impaired cellular proliferation. We examined signaling pathways downstream of BMP7; the level of cortical phosphorylated Smad1, 5, and 8 was unchanged in BMP CKO kidneys, but phosphorylated p38 mitogen-activated protein kinase was significantly decreased. In addition, ␤-catenin was reduced in BMP7 CKO kidneys, and its localization to intracellular vesicles suggested that it had been targeted for degradation. In summary, these results define a BMP7-mediated regulatory axis between glomeruli and proximal tubules during kidney development.

SummaryLaminin α5 influences the architecture of the mouse small intestine mucosa

The organization of the lining of the gastrointestinal tube is similar for the stomach, small intestine and colon. It is composed of a continuous simple epithelium and underlying mesenchyme, including blood vessels, fibroblasts/myofibroblasts and immune cells. Individual organs contain modifications of this mucosa that are critical for their functions. We hypothesize that changes in the composition of the epithelial basement membrane are a critical determinant for structure and function of the local mucosa. Laminins are excellent candidates for such a role, as they comprise a large family of αβ γ heterotrimeric glycoproteins that demonstrate developmental, organ and cell type specificity. We have found that adult mice lacking the normal villus laminin, α5, demonstrate a compensatory increase in α1 and α4, which are normally present in the colon. This laminin switch results in colonic metaplasia of the distal small intestine, which showed deepened crypts, villus atrophy and subsequent replacement by flat surface epithelial structures, and expression of colonic markers. This change was associated with aberrant intestinal epithelial cell proliferation, differentiation and migration. Here, unlike pathologic processes in humans that result in colonic metaplasia, there was no infiltration of inflammatory cells. These observations highlight the important and distinct roles of different laminin isoforms on the patterning of intestinal crypt‐villus architecture and the regulation of intestinal epithelial cell behavior. Our data also suggest that differences in laminin composition along the gut's rostrocaudal axis contribute to its regionalization into small and large intestine.