Intrinsic and extrinsic regulation of cranial mesoderm

描述(申请人提供)：颅神经脊细胞是一种多能的移行细胞群，它产生了头和面部的大部分骨、软骨、结缔组织和周围神经系统。颅面畸形(如第一弓综合征、腭裂、颅缝畸形)约占所有先天性畸形的三分之一，因此在很大程度上可归因于神经脊细胞的形成、迁移、增殖和分化方面的缺陷。为了了解颅面畸形的起源并开发治疗或干预方法，这是人类的关键健康问题，了解调节脑神经脊细胞和头部发育的遗传和细胞机制至关重要。复杂的遗传和细胞分析已经确定，神经脊细胞模式是由神经管在形成过程中获得的信号以及在迁移和分化过程中接触的组织接收的信号的平衡决定的。颅骨中胚层是一种与迁移的神经脊细胞广泛相互作用的组织，最近被证明是决定小鼠神经脊细胞的身份和迁移特征的关键因素。这一观点认为，由于神经脊细胞发育缺陷而导致的颅面畸形，往往是颅骨中胚层等组织的原发缺陷的次要后果。因此，这一建议的主要目标是表征调节颅骨中胚层模式的内在和外在线索，这将为神经脊细胞发育、颅面形态发生和颅面畸形的起源提供独特的见解。我们正在采取一种免费的方法，将通过基因芯片阵列在小鼠中发现中胚层特异性基因与中胚层切除和移植结合起来，并在小鼠颅面畸形模型中进行分析，以测试神经脊细胞、鳃弓和颅面发育期间颅中胚层的组织和基因特异性功能。

DESCRIPTION (provided by applicant): Cranial neural crest cells are a multipotent migratory cell population which generate the majority of the bone, cartilage, connective tissue and peripheral nervous system of the head and face. Craniofacial abnormalities (ex, first arch syndrome, cleft palate, craniosynostoses) account for approximately one-third of all congenital anomalies and therefore are largely attributable to defects in the formation, migration, proliferation and differentiation of neural crest cells. In order to comprehend the origins of craniofacial abnormalities and develop treatments or methods of intervention, which are critical human health issues, it is vital to understand the genetic and cellular mechanisms that regulate cranial neural crest cell and head development. Sophisticated genetic and cellular analyses have determined that neural crest cell patterning is governed by a balance of signals acquired in the neural tube during their formation together with signals received from the tissues they contact during their migration and differentiation. The cranial mesoderm is one such tissue that interacts extensively with the migrating neural crest cells and recently has been demonstrated to be a key player in patterning both the identity and migration characteristics of neural crest cells in mice. This argues that craniofacial abnormalities, which are attributed to defects in neural crest cell development, may often be the secondary consequence of primary defects in tissues such as the cranial mesoderm. Therefore, the primary goal of this proposal is to characterize the intrinsic and extrinsic cues that regulate cranial mesoderm patterning which will provide unique insights into neural crest cell development, craniofacial morphogenesis, and the origins of craniofacial abnormalities. We are taking a complimentary approach combining mesoderm specific gene discovery via gene chip arrays in mice with mesoderm ablations and transplantations together with analyses in mouse models of craniofacial malformation to test for tissue and gene specific function of the cranial mesoderm during neural crest cell, branchial arch, and craniofacial development.