Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
In this study we have developed an exvivo lung explant system, where distal lung tissue from E18.5 Glucocorticoid Receptor (GR)-null mice have been exposed to at-RA. Whole genome microarrays and quantitative Real-time PCR have been utilized to identify and confirm GR-antagonised RA-responsive genes.Only the common rarb2/4 transcript and tcf15 (paraxis) were found to match this criteria. We propose that the antagonistic effects on alveolarisation by GC and RA are regulated by signaling through the rarb2/4-promoter. Furthermore, the transcriptional activation of some RA-responsive genes was dependent on the presence of GR. These genes include the RA-metabolising enzymes cyp1a1 and cyp7b1, the tight junction proteins cldn5 and cldn4 and the ECM-protein eln. These studies will provide a better understanding of the processes involved in alveolar development and the specific roles of GC-and RA-signaling.These findings may impact on the procedures used in the care of premature infants, and hence reduce the effects of respiratory distress syndrome.We have shown previously that Sox3 is expressed in the progenitor cells of the embryonic CNS and functions as a dosagedependent regulator of CNS development in mice and man. To further investigate the role of SOX3, we generated transgenic mice that contain multiple copies of a 36 kb Sox3 genomic fragment. Unexpectedly, progeny from one line (termed Sex reversed (Sr)) exhibited a markedly distorted sex ratio in favour of male offspring (77% (102/133) of Tg/+ XX adults were male). Analysis of the reproductive tract in adult sex-reversed animals indicated that all male-specific structures were present, indicating complete XX male sex reversal. Transgene expression analysis in Sr embryos demonstrated that Sox3 is ectopically upregulated in the primordium of XX and XY gonads during the sex determining window (approximately 11.0-11.25 dpc) and is expressed in the ertoli cell lineage until at least 15.5 dpc. Transgene expression in the gonad appears to be influenced by regulatory elements associated with genes that flank the integration site on chromosome 19, which may serve to reinforce testis fate determination.Importantly, morphological, gene expression and co-transfection studies indicate that SOX3 induces testis differentiation in Sr embryonic gonads by activation of Sox9 in a mechanism analo-gous to that used by the Y-linked sex determining gene Sry.Together, these data suggest that SOX3 and SRY proteins are functionally interchangeable in sex determination and provide support for the notion that Sry evolved from Sox3 via a regulatory mutation that led to its de novo expression in the early gonad. Bi-allelic mutations inWt1 combined with activating mutations in the b-catenin proto-oncogene are responsible for 15-20% of cases of Wilms' tumours. To understand the effect of Wt1 loss and b-catenin activation on kidney development and tumour development, we are currently analyzing a collection of mouse models using different Cre lines to inactivate Wt1 and/or activate mutant b-cateni...
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