Genetic regulation of embryonic head mesenchyme patterning

摘要 颅骨（颅骨的上部）包括骨板和纤维关节（缝合线和<$anels）， 这两个组成部分之间的平衡至关重要。颅缝早闭（缝线过早脱落）发生在 出生率为1/2000，并导致畸形头骨，可进一步影响大脑和口面 发展目前颅缝早闭的治疗通常涉及在年轻时进行侵入性手术， 发病率甚至死亡率都很高因此，改进针对这一缺陷的干预方法， 对公众健康非常重要。我们研究的长期目标是获得全面的 理解颅骨发育的分子遗传调控，这可以导致创新 治疗和预防相关出生缺陷的战略。 在胚胎发育过程中，头盖骨的头间充质原基完全包裹 大脑在早期阶段。随后，颅骨开始从上的间充质发育。 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”）， 间充质细胞（EMM）并不启动骨化，只对软组织如骨缝起作用 和真皮。骨形成的这种空间限制对于形成正确的颅骨至关重要 因为它允许顶点被缝合线和囟门而不是骨头占据。迄今为止， 关于在头部发展计划中造成这种区域差异的因素， 间充质 根据我们的初步数据，我们假设EMM本质上是抵抗 成骨诱导，LMX 1B（LIM同源框转录因子1b）是一个关键的抗成骨因子， 这个背景。因此，本提案的目标是阐明控制细胞凋亡的分子机制。 EMM的成骨能力，重点是LMX 1B。我们将定义的空间和时间特异性 LMX 1B在颅骨发育过程中的功能，并研究LMX 1B对颅骨发育过程中LMX 1B功能的影响。 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 到EMM和SOM，并确定Lmx 1b下游的遗传网络，调节这种模式的头部 间充质 我们的研究结果将为颅骨发育的早期阶段的调控提供重要的见解。 开发和确定新的机制和球员，可以有助于发病机制， 颅缝早闭

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.