Understanding how the master transcriptional regulator HOXA5 defines cell fate in the developing embryo

适当控制细胞类型特异性转录程序对正常发育至关重要。单个转录调节因子的突变通常会产生多效表型，并具有器官特异性后果。因此，了解单个转录因子如何通过控制特定的转录程序来赋予细胞和组织其身份是至关重要的。HOX蛋白是一种进化保守的转录因子，在胚胎发生、器官发生和产后组织稳态中起着关键作用。它们的突变导致多种发育缺陷和疾病。尽管HOX蛋白在许多细胞类型中广泛表达，但它们的调节功能依赖于环境。它们与相似的富含TNAT基元的dna结合位点结合，但在体内赋予不同的调控作用，这就提出了如何获得HOX转录输出特异性的基本问题。虽然Hox基因的发育作用已经确定，但了解它们如何起作用仍有待于靶基因的鉴定。因此，HOX蛋白代表了确定单个转录因子如何控制细胞命运的理想候选者。我们的长期目标是确定HOX转录因子如何在哺乳动物发育过程中以高度依赖环境的方式调节靶基因表达。我们使用HOXA5作为模型，因为在小鼠中HOXA5基因功能的丧失会导致过多的特征明确的表型，最重要的是，由于呼吸系统畸形的组合而导致出生时死亡。这些缺陷包括由软骨异常引起的气管闭塞，由分支减少、发育不全和细胞分化异常引起的肺畸形，以及膈神经支配和肌肉组织的改变。这些表型引起严重的人类疾病，如气管狭窄，肺发育不全和横膈膜膨出。没有其他单一的Hox突变体表现出如此明显的呼吸系统表型，揭示了Hoxa5在这一发育过程中的功能优势。Hoxa5在呼吸系统中的多性作用提示细胞特异性机制，并使Hoxa5成为研究单个HOX蛋白如何实现细胞特异性以协调器官系统发育的理想模型。我们假设HOXA5转录因子通过激活共同的转录程序来发挥其部分功能，但也通过调节不同的、特定于环境的效应物来发挥其功能。我们的目标是确定在呼吸系统形成过程中参与HOXA5作用的分子机制，以阐明HOXA5如何获得功能性细胞特异性。我们的目标是：鉴定和比较发育中的气管、肺和横膈膜中由HOXA5主调控因子控制的基因网络2。在气管形成的特定背景下确定HOXA5功能的遗传和细胞机制

Proper control of cell-type specific transcriptional programs is critical for normal development. Mutation of a single transcriptional regulator often produces pleiotropic phenotypes with organ-specific consequences. Therefore, it is fundamental to understand how a single transcription factor confers to cells and tissues their identity by controlling specific transcriptional programs. HOX proteins are evolutionary conserved transcription factors that play critical roles in embryogenesis, organogenesis and tissue homeostasis during postnatal life. Their mutations lead to multiple and various developmental defects and diseases. Despite their broad expression in numerous cell types, HOX proteins perform their regulatory functions in a context-dependent fashion. They bind to similar TNAT motif-rich DNA-binding sites, but confer different regulatory actions in vivo, raising the fundamental question of how specificity of HOX transcriptional outputs is attained. While the developmental role of Hox genes is established, understanding how they act still awaits the identification of target genes. Thus, HOX proteins represent ideal candidates to determine how individual transcription factors govern cell fate. Our long-term objective is to define how HOX transcription factors regulate target gene expression in a highly context-dependent manner during mammalian development. We use HOXA5 as a model, because the loss of Hoxa5 gene function in mice results in a plethora of well-characterized phenotypes and, most importantly, in death at birth due to the combination of respiratory system malformations. These defects include trachea occlusion resulting from cartilage anomalies, lung dysmorphogenesis due to reduced branching, hypoplasia and abnormal cell differentiation, and altered diaphragm innervation and musculature. These phenotypes evoke severe human diseases such as tracheal stenosis, lung hypoplasia and diaphragm eventration. No other single Hox mutants present such an overt respiratory system phenotype revealing the functional predominance of Hoxa5 in this developmental process. Hoxa5 pleiotropic action in the respiratory system suggests cell-specific mechanisms, and makes Hoxa5 an ideal model for studying how individual HOX proteins achieve cell-specificity to orchestrate organ system development. We hypothesize that HOXA5 transcription factor exerts part of its functions through activation of common transcriptional programs but also via the regulation of distinct, context-specific effectors. Our objectives are to define the molecular mechanisms involved in HOXA5 action during the formation of the respiratory system in order to elucidate how HOXA5 attains functional cell-specificity. Our aims are to: 1.Identify and compare the gene networks controlled by the HOXA5 master regulator in the developing trachea, lung and diaphragm 2.Determine the genetic and cellular mechanisms of HOXA5 function in the specific context of trachea formation