Biomedical subjects

M Rauchman

Publications and source records attributed to M Rauchman.

6 recordsLinked to original sources

PubMed2001

Exclusion of SIX6 hemizygosity in a child with anophthalmia, panhypopituitarism and renal failure.

We report a patient who presented with anophthalmia, panhypopituitarism, early onset of end stage renal failure, and craniofacial abnormalities. MRI at age 3 revealed that the pituitary was absent and renal biopsy demonstrated nephronophthisis as the cause of the renal failure. A similar syndrome has been associated with interstitial deletions of chromosome 14q22 and in one case hemizygosity for SIX6 was demonstrated. The patient reported here had a normal karyotype and Southern blot did not reveal loss of one copy of SIX6. We discuss other possible candidate genes that could be implicated in this syndrome.

Abnormalities, Multiple↗

PubMed2000

The role of homeobox genes in kidney development.

Homeodomain-containing transcription factors are essential for a variety of processes in vertebrate development, including organogenesis. They have been shown to regulate cell proliferation, pattern segmental identity and determine cell fate decisions during embryogenesis. During nephrogenesis, homeobox genes play an important role at multiple developmental stages, from the early events in intermediate mesoderm to terminal differentiation of glomerular and tubular epithelia. Increasingly sophisticated genetic approaches will probably reveal additional functions for this class of transcription factors in the developing kidney and lead to the identification of critical downstream target genes.

Animals↗

PubMed1999

BMP7 acts in murine lens placode development.

Targeted inactivation of the Bmp7 gene in mouse leads to eye defects with late onset and variable penetrance (A. T. Dudley et al., 1995, Genes Dev. 9, 2795-2807; G. Luo et al., 1995, Genes Dev. 9, 2808-2820). Here we report that the expressivity of the Bmp7 mutant phenotype markedly increases in a C3H/He genetic background and that the phenotype implicates Bmp7 in the early stages of lens development. Immunolocalization experiments show that BMP7 protein is present in the head ectoderm at the time of lens placode induction. Using an in vitro culture system, we demonstrate that addition of BMP7 antagonists during the period of lens placode induction inhibits lens formation, indicating a role for BMP7 in lens placode development. Next, to integrate Bmp7 into a developmental pathway controlling formation of the lens placode, we examined the expression of several early lens placode-specific markers in Bmp7 mutant embryos. In these embryos, Pax6 head ectoderm expression is lost just prior to the time when the lens placode should appear, while in Pax6-deficient (Sey/Sey) embryos, Bmp7 expression is maintained. These results could suggest a simple linear pathway in placode induction in which Bmp7 functions upstream of Pax6 and regulates lens placode induction. At odds with this interpretation, however, is the finding that expression of secreted Frizzled Related Protein-2 (sFRP-2), a component of the Wnt signaling pathway which is expressed in prospective lens placode, is absent in Sey/Sey embryos but initially present in Bmp7 mutants. This suggests a different model in which Bmp7 function is required to maintain Pax6 expression after induction, during a preplacodal stage of lens development. We conclude that Bmp7 is a critical component of the genetic mechanism(s) controlling lens placode formation.

Animals↗

PubMed1998

Induction of Rb-associated protein (RbAp46) by Wilms' tumor suppressor WT1 mediates growth inhibition.

The Wilms' tumor suppressor gene, wt1, encodes a zinc-finger transcription factor, WT1, that plays an important role in controlling urogenital development. Previously, WT1 has been shown to inhibit cell growth and to repress transcription initiated from the promoters of a number of growth-promoting genes. However, few physiological target genes that are transcriptionally activated by WT1 have been established. Using suppression subtractive hybridization polymerase chain reaction, we isolated a WT1 target gene that is up-regulated about 15-fold in cells expressing WT1. The gene was identified as retinoblastoma suppressor (Rb)-associated protein 46 (RbAp46), a nuclear protein that interacts physically with Rb and is a component of the human mSin3 co-repressor complex. Cells transfected with RbAp46 cDNA formed fewer colonies than the control cells, and RbAp46 suppressed the growth rate (by about 2-fold) of transfected cells. In the developing kidney and gonad, RbAp46 exhibits an expression pattern similar to that of WT1. We conclude that RbAp46 has strong growth inhibition activity and may function as an important mediator of WT1's function.

Animals↗

PubMed1998

Lens-specific gene recruitment of zeta-crystallin through Pax6, Nrl-Maf, and brain suppressor sites.

Zeta-Crystallin is a taxon-specific crystallin, an enzyme which has undergone direct gene recruitment as a structural component of the guinea pig lens through a Pax6-dependent mechanism. Tissue specificity arises through a combination of effects involving three sites in the lens promoter. The Pax6 site (ZPE) itself shows specificity for an isoform of Pax6 preferentially expressed in lens cells. High-level expression of the promoter requires a second site, identical to an alphaCE2 site or half Maf response element (MARE), adjacent to the Pax6 site. A promoter fragment containing Pax6 and MARE sites gives lens-preferred induction of a heterologous promoter. Complexes binding the MARE in lens nuclear extracts are antigenically related to Nrl, and cotransfection with Nrl elevates zeta-crystallin promoter activity in lens cells. A truncated zeta promoter containing Nrl-MARE and Pax6 sites has a high level of expression in lens cells in transgenic mice but is also active in the brain. Suppression of the promoter in the brain requires sequences between -498 and -385, and a site in this region forms specific complexes in brain extract. A three-level model for lens-specific Pax6-dependent expression and gene recruitment is suggested: (i) binding of a specific isoform of Pax6; (ii) augmentation of expression through binding of Nrl or a related factor; and (iii) suppression of promoter activity in the central nervous system by an upstream negative element in the brain but not in the lens.

Animals↗

PubMed1994

Regulation of mitogenesis, motogenesis, and tubulogenesis by hepatocyte growth factor in renal collecting duct cells.

Hepatocyte growth factor (HGF) has been implicated in branching tubulogenesis of the developing kidney and in response to renal injury. We therefore examined the effects of response to renal injury. We therefore examined the effects of HGF on a recently described murine inner medullary collecting duct epithelial cell line (mIMCD-3 cells) in comparison with Madin-Darby canine kidney (MDCK) cells. HGF induced mitosis, scattering, and tubulogenesis in both mIMCD-3 cells and MDCK cells. However, mIMCD-3 cells underwent branching tubulogenesis under matrix conditions that did not support these morphogenetic changes in MDCK cells, suggesting substantial differences in regulation of tubulogenesis in these two cell types. In quiescent mIMCD-3 cells, the high-affinity receptor for HGF, c-met, was expressed in a nonphosphorylated state. After stimulation with HGF, there was a > 10-fold increase in receptor tyrosine phosphorylation and selective association with at least two intracellular proteins, including the phosphatidylinositol-3-kinase. Thus mIMCD-3 cells, which undergo HGF-dependent mitosis, scattering, and branching tubulogenesis, express the c-met receptor in a highly regulated state and therefore should make an excellent model for examining the mechanisms of HGF-dependent tubulogenesis in the renal collecting duct.

Animals↗