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Mutations in the transcription factor Pdx1 cause maturity-onset diabetes of the young 4 (MODY4). Islet transduction with dominant-negative Pdx1 (RIPDN79PDX1) impairs mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). Transcript profiling revealed suppression of nuclear-encoded mitochondrial factor A (TFAM). Herein, we show that Pdx1 suppression in adult mice reduces islet TFAM expression coinciding with hyperglycemia. We define TFAM as a direct target of Pdx1 both in rat INS1 cells and human islets. Adenoviral overexpression of TFAM along with RIPDN79PDX1 in isolated rat islets rescued mitochondrial DNA (mtDNA) copy number and restored respiratory chain activity as well as glucose-induced ATP synthesis and insulin secretion. CGP37157, which blocks the mitochondrial Na(+)/Ca(2+) exchanger, restored ATP generation and GSIS in RIPDN79PDX1 islets, thereby bypassing the transcriptional defect. Thus, the genetic control by the beta cell-specific factor Pdx1 of the ubiquitous gene TFAM maintains beta cell mtDNA vital for ATP production and normal GSIS.
Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.
Targeted mutagenesis of Fgf9 in mice causes male-to-female sex reversal. Among the four FGF receptors, FGFR2 showed two highly specific patterns based on antibody staining, suggesting that it might be the receptor-mediating FGF9 signaling in the gonad. FGFR2 was detected at the plasma membrane in proliferating coelomic epithelial cells and in the nucleus in Sertoli progenitor cells. This expression pattern suggested that Fgfr2 might play more than one role in testis development. To test the hypothesis that Fgfr2 is required for male sex determination, we crossed mice carrying a floxed allele of Fgfr2 with two different Cre lines to induce a temporal or cell-specific deletion of this receptor. Results show that deletion of Fgfr2 in embryonic gonads phenocopies deletion of Fgf9 and leads to male-to-female sex reversal. Using these two Cre lines, we provide the first genetic evidence that Fgfr2 plays distinct roles in proliferation and Sertoli cell differentiation during testis development.
Genetic linkage studies in both bipolar affective disorder (BPAD) and schizophrenia have implicated overlapping regions of chromosome 22q. We previously reported that BPAD pedigrees containing multiple members with psychotic symptoms showed suggestive linkage to chromosome 22q12.3. Now we have tested 189 single nucleotide polymorphisms (SNPs) spanning a 3 Mb region around the linkage peak for association with BPAD in 305 families, unrelated cases, and controls. SNPs were selected in or near genes, resulting in coverage at a density of 1 SNP per 6.7 kb across the 22 annotated genes in the region. The strongest signal emerged from family-based association analysis of an 11-SNP, 54 kb haplotype straddling the gene HMG2L1 and part of TOM1. A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P = 0.0011) and with psychotic BPAD (allele-wise P = 0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotype-wise results for rs2413338 in HMG2L1 showed an empirical P = 0.037 for the difference between subsets. HMG2L1 is a negative regulator of Wnt signaling, a pathway of interest in psychotic BPAD as it is activated by both mood stabilizer and anti-psychotic medications. Further work is needed to confirm these results and uncover the functional variation underlying the association signal.
(c) 2007 Wiley-Liss, Inc.
Sox10 is an essential transcription factor required for development of neural crest-derived melanocytes, peripheral glia, and enteric ganglia. Multiple transcriptional targets regulated by Sox10 have been identified; however, little is known regarding regulation of Sox10. High sequence conservation surrounding 5' exons 1 through 3 suggests these regions might contain functional regulatory elements. However, we observed that these Sox10 genomic sequences do not confer appropriate cell-specific transcription in vitro when linked to a heterologous reporter. To identify elements required for expression of Sox10 in vivo, we modified bacterial artificial chromosomes (BACs) to generate a Sox10betaGeoBAC transgene. Our approach leaves endogenous Sox10 loci unaltered, circumventing haploinsufficiency issues that arise from gene targeting. Sox10betaGeoBAC expression closely approximates Sox10 expression in vivo, resulting in expression in anterior dorsal neural tube at embryonic day (E) 8.5 and in cranial ganglia, otic vesicle, and developing dorsal root ganglia at E10.5. Characterization of Sox10betaGeoBAC expression confirms the presence of essential regulatory regions and additionally identifies previously unreported expression in thyroid parafollicular cells, thymus, salivary, adrenal, and lacrimal glands. Fortuitous deletions in independent Sox10betaGeoBAC lines result in loss of transgene expression in peripheral nervous system lineages and coincide with evolutionarily conserved regions. Our analysis indicates that Sox10 expression requires the presence of distant cis-acting regulatory elements. The Sox10betaGeoBAC transgene offers one avenue for specifically testing the role of individual conserved regions in regulation of Sox10 and makes possible analysis of Sox10+ derivatives in the context of normal neural crest development.
(c) 2006 Wiley-Liss, Inc.
Mutations in the transcription factor Sox10 or Endothelin Receptor B (Ednrb) result in Waardenburg Syndrome Type IV (WS-IV), which presents with deficiencies of neural crest derived melanocytes (hypopigmentation) and enteric ganglia (hypoganglionosis). As Sox10 and Ednrb are expressed in mouse migratory neural crest cells and melanoblasts, we investigated the possibility that SOX10 and EDNRB function through a hierarchical relationship during melanocyte development. However, our results support a distinct rather than hierarchical relationship. First, SOX10 expression continues in Ednrb null melanoblasts, demonstrating that SOX10 expression is not dependent on EDNRB function. Second, Ednrb expression persists in E10.5 Sox10null embryos, demonstrating that Ednrb is not dependent on SOX10 for expression in migratory neural crest cells. Third, over-expression of SOX10 in melanoblasts of mice that harbor null or hypomorphic Ednrb alleles does not rescue hypopigmentation, suggesting that SOX10 overexpression can neither complement a lack of EDNRB function nor increase Ednrb expression. Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes. Our results suggest that SOX10 does not directly activate Ednrb transcription in the melanocyte lineage. Given that SOX10 directly activates Ednrb in the enteric nervous system, our results suggest that SOX10 may differentially activate target genes based on the particular cellular context.
Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.
Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence of multiple gene interactions that modulate the ability of enteric neural crest (NC) cells to populate the developing gut. One of the essential genes for this process is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic background show variation in penetrance and expressivity of enteric aganglionosis that are analogous to the variable aganglionosis seen in human HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this variation arises from modifiers in the genetic background. To determine whether known HSCR susceptibility loci are acting as modifiers of Sox10, we tested for association between genes in the endothelin signaling pathway (EdnrB, Edn3, Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom mice. Single locus association analysis in this pedigree identifies interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The presence of C57BL/6J alleles at EdnrB is associated with increased penetrance and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and Sox10 mutants corroborate this gene interaction with double mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant progeny implying the action of additional modifiers on this phenotype. Our data demonstrates that Sox10-EdnrB interactions can influence development of the enteric nervous system in mouse models and suggests that this interaction could contribute to the epistatic network producing variation between patients with aganglionosis.
Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon. One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB). The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon. In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR, in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.
While mutations in Sox4, a member of the SRY-like HMG box gene family, have been associated with a variety of human disorders and embryonic defects in the mouse, the structure and developmental expression of Sox4 in the avian embryo has not been described. We have isolated and characterized the chicken Sox4 gene. The chicken Sox4 gene shows a high degree of sequence homology with the mouse and human Sox4 genes, particularly in the HMG-like DNA binding domain and at the carboxy terminus. Furthermore, our in situ hybridization studies document an expression pattern during embryonic development that is very similar to that described for the mouse, particularly with regards to expression in the developing heart. However, abundant expression was also detected in tissues of neural crest origin including pharyngeal arch and craniofacial mesoderm, supporting a potential primary role in neural crest cardiac pathology previously detected in Sox4 mutant mice. Furthermore, a reciprocal pattern of Sox4 and Sox11 expression in the developing neural tube was detected in the chicken compared to that seen in the mouse. These studies suggest that Sox4 plays an important and conserved role in the embryonic development of these structures in the chicken as well as in the mouse and lay the foundation for future studies of the role of Sox4 during critical events of organogenesis.