Suchergebnisse

Lucena, Jaume et. alt. 10 p.-4 fig-.1 tab. ; [Background] GTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neurodevelopmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice. ; [Methods] By gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients. ; [Results] Homozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs. ; [Conclusion] Our data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model. ; This work was supported by grants from the Spanish Ministry of Health (FIS 04/0433, to VC), the Spanish Ministry of Science and Education (SAF2004-6382, to LPJ and BFU2006-04406/BMC, to JLB) and the VI Framework Programme of the European Union (LSHG-CT-2006-037627, to LPJ). JL was supported by a FPI Fellowship (SAF2001-3941) and VC is a FIS Investigator. ; Peer reviewed

59 p.-8 fig. Título del preprint:The gene doublesex of dipteran Sciara does not follow the expression pattern observed in insects. ; The gene doublesex, which is placed at the bottom of the sex determination gene cascade, plays the ultimate discriminatory role for sex determination in insects. In all insects where this gene has been characterized, the dsx pre-mRNA follows a sex-specific splicing pattern producing male- and female-specific mRNAs, encoding the male-DSXM and female-DSXF proteins,which determine male and female development, respectively. The present paper reports the isolation and characterization of the gene doublesex of dipteran Sciara insects. The Sciara doublesex gene is constitutively transcribed during development and adult life of males and females. Sciara had no sex-specific doublesex mRNAs but the same transcripts, produced by alternative splicing of its primary transcript, were present in both sexes, although their relative abundance is sex-specific. However, only the female DSXF protein, but not the male DSXM protein, was produced at similar amounts in both sexes. An analysis of the expression of female and male Sciara DSX proteins in Drosophila showed that these proteins conserved female and male function, respectively, on the control of Drosophila yolk-protein genes. The molecular evolution of gene doublesex of all insects where this gene has been characterized revealed that Sciara doublesex displays a considerable degree of divergence with respect to the rest of dipterans, as suggested by its basal position within the doublesex phylogeny, its gene organization and its splicing pattern. It is proposed that if the gene doublesex were needed for Sciara sex determination, this gene would not play the ultimate discriminatory role for sex determination performed in insects. ; L Sánchez had financial support (BFU2005-03000 and BFU2008-00474) from the Spanish government during the time the group was doing the work presented in this manuscript. However, he had to close his laboratory —with the consequent disappearance of the group— because his grant was not renewed it due to the economical crisis in Spain. L Sánchez thanks very much to JL Barbero for permitting us to finish this work in his laboratory and sponsored by his grant. ; No