Le gène hairless (hr) des mammifères code pour une protéine nucléaire impliquée dans le contrôle du renouvellement du follicule pileux. Cette protéine est un cofacteur de récepteurs nucléaires d’hormones qui régulent la transcription de gènes cibles au cours de la différentiation de l’épiderme et du cycle du poil. La protéine Hairless (HR) fait partie de grands complexes multiprotéiques capables de réprimer la transcription, en association avec des facteurs de remodelage de la chromatine comme les histones désacétylases. Chez les mammifères, le locus hairless est la cible de nombreuses mutations alléliques dont les effets sont pléiotropiques. Ces altérations entraînent l’apparition d’un phénotype cutané complexe, caractérisé par la perte progressive et irréversible d’un pelage d’apparence normale au cours des premières semaines de vie post-natale. L’analyse de la littérature sur le gène hairless chez la souris et chez l’homme permet d’attribuer des différences morphologiques spécifiques à chaque mutant, aussi bien au niveau de l’épiderme et du follicule pileux que dans d’autres tissus où le gène est exprimé au cours du développement. Ces résultats suggèrent que l’intégrité du gène hairless est requise pour le déroulement correct de la morphogenèse d’organes aussi différents que l’épiderme, l’oreille interne, l’ovaire ou le thymus. Le gène hairless semble ainsi faire partie de circuits et de cascades d’interactions géniques dont le contrôle moléculaire est fondamentalement inconnu. La variété des phénotypes alléliques souligne l’importance de l’analyse moléculaire du locus hairless pour identifier les altérations géniques impliquées dans les différentes mutations détectées. Les recherches concernant la mutation hairless ont été particulièrement dynamiques pendant les dernières années, depuis que l’homologue de ce gène a pu être mis en évidence chez l’homme. Cependant, un bon nombre de questions reste en suspens, notamment quant au site exact d’activité du gène hairless au sein des nombreuses populations cellulaires du follicule pileux, son rôle précis au cours de la morphogenèse, sa localisation au sein des voies de signalisation, ainsi que l’identité des partenaires et des cibles de la protéine Hairless.
High-level expression of the human growth hormone (hGH) gene is limited to somatotrope and lactosomatotrope cells of the anterior pituitary. We previously identified a locus control region (LCR) for the hGH gene composed of four tissue-specific DNase I-hypersensitive sites (HS) located between −14.6 kb and −32 kb 5′ to the hGH transcription start site that is responsible for establishing a physiologically regulated chromatin domain for hGH transgene expression in mouse pituitary. In the present study we demonstrated that the LCR mediates somatotrope and lactosomatotrope restriction on an otherwise weakly and diffusely expressed hGH transgene. The subregion of the LCR containing the two pituitary-specific HS, HSI and HSII (−14.6 to −16.2 kb relative to the hGH promoter and denoted HSI,II), was found to be sufficient for mediating somatotrope and lactosomatotrope restriction, for appropriately timed induction of hGH transgene expression between embryonic days 15.5 and 16.5, and for selective extinction of hGH expression in mature lactotropes. When studied by cell transfection, the HSI,II fragment selectively enhanced transcription in a presomatotrope-derived cell line, although at levels (2- to 3-fold) well below that seen in vivo . The LCR activity of the HSI,II element was therefore localized by scoring transgene expression in fetal founder pituitaries at embryonic day 18.5. The data from these studies indicated that a 404-bp segment of the HSI,II region encodes a critical subset of LCR functions, including the establishment of a productive chromatin environment, cell-specific restriction and enhancement of expression, and appropriately timed induction of the hGH transgene during embryonic development.
The formation and patterning of mesoderm during mammalian gastrulation require the activity of Nodal, a secreted mesoderm-inducing factor of the transforming growth factor-beta (TGF-beta) family. Here we show that the transcriptional corepressor DRAP1 has a very specific role in regulation of Nodal activity during mouse embryogenesis. We find that loss of Drap1 leads to severe gastrulation defects that are consistent with increased expression of Nodal and can be partially suppressed by Nodal heterozygosity. Biochemical studies indicate that DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription factor FoxH1 (FAST), a critical component of a positive feedback loop for Nodal activity. We propose that DRAP1 limits the spread of a morphogenetic signal by down-modulating the response to the Nodal autoregulatory loop.
We have previously identified a novel mutation in the mouse hairless locus – hairless rhino bald Mill Hill., symbol hrrhbmh. The genetic alteration in these mice consists in a large 249 bp deletion at the 3′ part of exon 19 of the hairless gene. Here we show that this deletion removes the stop codon, and modify the reading frame of the hairless protein, generating a mutant protein, harbouring an additional sequence of 117 amino acids. The hairless gene mRNA is normally expressed during the embryonic and post-natal development of the bmh mice hair follicle. However, the gene product displays abnormal cellular localisation in various types of cells in culture and in the epidermis of bmh mutant mice during post-natal development. We demonstrate that the mutant protein is able to interact with TRs and VDRs nuclear hormone receptors in the cytoplasm and its translocation to the nucleus is essential for a normal function. Using a specific anti-Hr antibody, we perform detailed time-course analysis of the wild-type and mutant protein localisation in the developing hair follicle structures. We discuss the relevance of the hairless protein mis-localization to the specific skin phenotype and stress the impact of these data with respect to the molecular basis of the pathology in mouse hairless mutants. Our findings reveal a complex molecular network that potentially links several signalling pathways underlying hair follicle formation.
