Lateral plate mesoderm expression in the cervico-upper thoracic region

A complex organization of overlapping transcriptional units encompassing the Hoxa5 locus exists, which results from alternative splicing and the use of three promoters, one proximal Gabapentin producing the 1.8-kb transcript and two distal ones giving rise to long noncoding RNAs. Using a transgenic approach, we have identified regulatory elements directing the developmental expression of the Hoxa5 proximal promoter. An 11.1-kb genomic fragment can recapitulate the temporal expression and substantially reconstitute the spatial pattern of the 1.8-kb Hoxa5 transcript in mouse embryos. It includes DNA Warfarin sodium control sequences, such as the 604-bp brachial spinal cord enhancer and a 650-bp temporal control region, both contained in the Hoxa5 59 flanking sequences. A 2.1-kb mesodermal enhancer important for Hoxa5 paraxial and lateral plate mesoderm expression in the cervico-upper thoracic region of the A-P axis is positioned 39 of the Hoxa5 gene. CDX proteins bind this sequence acting as potential regulators for the regionalization of Hoxa5 gene expression along the axis. A 1.5-kb DNA region that targets Hoxa5 lung and gut developmental expression was also identified in the Hoxa4-Hoxa5 intergenic sequences. Several Hox genes, mainly from paralog groups 1 to 8, are expressed along the respiratory tract. However except for Hoxa5, the lack of overt lung phenotype in single Hox mutants indicates that Hoxa5 plays a predominant function in lung ontogeny. The prevalent role of Hoxa5 in organ development prompted us to further characterize Hoxa5 lung and gut regulatory sequences. Here, we present evidence that Hoxa5 lung and gut expression is under the control of several DNA elements. Some are shared with the flanking Hoxa4 gene and they bind the transcription factor YY1, which acts as a positive regulator of Hoxa5 gene expression in the developing lung and gut. Traumatic brain injury remains a major cause of morbidity, mortality and long-term disability in children and young adults. It imposes a significant threat to the lives of patients, remains a profound and long-lasting social and economic consequence and is poorly treated by currently available drugs.

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