Genetic regulation of embryonic head mesenchyme patterning

摘要 头盖骨(头骨的上部)由骨板和纤维关节(缝线和颧骨)组成，以及 这两个组成部分之间的平衡至关重要。颅缝融合(过早脱线(S)) 出生频率为1/2000，这会导致头骨变形，进而影响大脑和口腔面部 发展。目前颅缝融合症的治疗通常涉及年轻时的侵入性手术，具有风险。 严重的发病率甚至死亡率。因此，改进对这一缺陷的干预方法是 对公众健康非常重要。我们研究的长期目标是获得全面的 了解颅骨发育的分子遗传调控，可以带来创新 治疗和预防相关出生缺陷的策略。 在胚胎发育过程中，头盖骨的头部间充质原基完全被包裹。 从早期阶段开始的大脑。随后，颅骨开始从上至下的间质发育。 位于眼睛上方的大脑外侧(眶上间充质，SOM)，并逐渐向 顶点。相反，间充质从一开始就位于顶点(‘早期迁移’)。 间充质，EMM)并不启动缝合，而只对缝线等软组织起作用。 还有真皮。这种骨形成的空间限制对于形成适当图案的头盖骨至关重要。 因为它允许顶点被缝线和颧骨占据，而不是骨骼。到目前为止，人们对此知之甚少 关于头部发展计划中这种地区差异的基础因素 间充质的我。 根据我们的初步数据，我们假设EMM本质上被编程为抵抗 Lmx1b(LIM Homeobox转录因子1b)是一种关键的抗骨诱导因子。 这一背景。因此，这一建议的目的是阐明控制细胞死亡的分子机制。 以Lmx1b为中心的EMM的成骨能力。我们将定义空间和时间的特殊性 Lmx1b在颅骨发育中的作用，并探讨Lmx1b对颅骨发育的影响。 成骨信号。此外，我们将使用全基因组方法来定义特定的遗传程序 EMM和SOM，并确定Lmx1b-调节这种头部图案的下游遗传网络 间充质的我。 我们的研究结果将为颅骨早期的调节提供重要的见解。 开发并确定新的机制和参与者，这些机制和参与者可能有助于 颅骨融合症。

ABSTRACT The calvaria (upper part of the skull) comprises plates of bone and fibrous joints (sutures and fontanels), and the balance between the two components is crucial. Craniosynostosis (premature loss of suture(s)) occurs at a frequency of 1/2000 births, and it leads to a dysmorphic skull that can further affect brain and orofacial development. Current treatment of craniosynostosis often involves invasive surgeries at young ages, with risks for significant morbidity and even mortality. Therefore, improving the methods of intervention for this defect is of great importance to public health. The long-term goal of our research is to obtain comprehensive understanding of the molecular genetic regulation of calvarial development, which can lead to innovative strategies to treat and prevent related birth defects. During embryonic development, the head mesenchyme primordium of the calvaria completely encases the brain from early stages. Subsequently, the calvarial bone starts to develop from the mesenchyme on the lateral sides of the brain just above the eye (`supra-orbital' mesenchyme, SOM), and expands gradually toward the vertex. In contrast, the mesenchyme positioned at the vertex from the beginning (`early migrating' mesenchyme, EMM) does not initiate ossficiation, and contributes only to the soft tissue such as the sutures and the dermis. This spatial restriction in bone formation is crucial to making the properly patterned calvaria because it allows the vertex to be occupied by sutures and fontanels instead of bone. To date, little is known about the factors that underlie this regional difference in the developmental program within the head mesenchyme. Based on our preliminary data, we hypothesize that EMM is intrinsically programmed to resist osteogenic induction, and that LMX1B (LIM homeobox transcription factor 1b) is a key anti-osteogenic factor in this context. Therefore, the goal of this proposal is to elucidate the molecular mechanism controlling the osteogenic competence of EMM with a focus on LMX1B. We will define the spatial and temporal specificity of LMX1B function during calvarial development, and investigate the effect of LMX1B on the function of osteogenic signals. Furthermore, we will use genome-wide approaches to define the genetic programs specific to EMM and SOM, and identify Lmx1b-downstream genetic network that regulates this patterning of the head mesenchyme. The outcome of our research will provide crucial insights into the regulation of early stages of calvarial development and identify novel mechanisms and players that can contribute to the pathogenesis of craniosynostosis.