Collaborative Research: Excellence in Research: Impact of Gbx2 on neural crest cells during neuronal, craniofacial and cardiovascular development

在脊椎动物的胚胎发育过程中，头部和心脏的发育紧密交织在一起。它们共享分子调控机制以及一些祖细胞群体。头部和心脏都是由大量细胞组成的，其中包括形成肌肉组织的中胚层细胞和形成结缔组织的神经嵴细胞。中胚层和神经嵴细胞对于头部和颈部的软骨和骨骼的发育以及心脏的适当分隔也很重要。构成这些组织的细胞的身份在胚胎发生过程中通过一组特定的基因（指定符）被指定，然后遵循它们的轨迹成为肌肉，结缔组织等。一个早期指定符，原肠胚形成-脑-同源异型框2（Gbx 2），对于神经嵴细胞的迁移（运动）和存活至关重要。神经嵴细胞和中胚层细胞在迁移过程中相互作用，形成头部和心脏结构。虽然中胚层细胞不受Gbx 2表达变化的直接影响，但神经嵴细胞受到影响并将改变与中胚层细胞的通讯，导致中胚层衍生结构的变化（例如，肌肉）。该项目旨在了解Gbx 2如何指导神经嵴发育，以及Gbx 2表达的变化如何影响头部（肌肉，软骨，骨骼，脑神经）和心脏发育。传统上，比较生物学、发育生物学和进化生物学领域在招收不同背景的学生和科学家方面一直不成功。该项目将促进这些生物学领域非传统背景的研究人员与历史上的黑人大学、霍华德大学和哥伦比亚特区大学之间的合作。 该奖项由美国国家科学基金会卓越研究计划资助。技术段颅神经嵴细胞（CNCC）参与颅神经节、颅神经、颅骨、头部肌肉结缔组织、心脏分隔、咽弓动脉发育等的发育。原肠胚-脑-同源盒（Gbx）转录因子家族成员Gbx 2调节多种发育过程，包括前后脑内的前后模式以及CNCC的迁移和存活。由于CNCC在头部和心脏发育过程中参与了许多不同的发育过程，因此该项目旨在分析Gbx 2直接控制下的靶基因，这些基因调节纯合Gbx 2neo胚胎中CNCC的迁移和存活。此外，该项目将包括分析Gbx 2表达变化对神经系统形态发生以及颅面和心血管结构的影响。后一部分具有重要意义，因为神经嵴细胞影响周围组织的发育和分化，反之亦然。在头部和毛发发育期间，CNCC和中胚层的相互作用对于该项目特别感兴趣，因为大多数头部和心脏肌肉组织的中胚层祖细胞来自共同的祖细胞区域，称为心咽区域。在Gbx 2以某种方式参与中胚层祖细胞场分化的基因调控网络的情况下，直接通过改变基因的转录或间接通过改变发育期间的神经嵴-中胚层相互作用，该项目将有助于深入了解调节头部和心脏发育以及颅神经节和神经发育的机制。该奖项反映了NSF的法定使命，通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Head and heart development are closely intertwined during embryonic development in vertebrates. They share molecular regulatory mechanism as well as some progenitor cell populations. Both head and heart, are made from a multitude of cells, which include mesodermal cells that form musculature and neural crest cells which form connective tissue. Mesodermal and neural crest cells are also important for the development of cartilages and bones in head and neck and for proper septation of the heart. The identity of cells that constitute these tissues is specified very early during embryogenesis via a specific set of genes (specifiers), then follow their trajectory to become muscle, connective tissue, etc.One early specifier, gastrulation-brain-homeobox 2 (Gbx2), is essential for the migration (movement) and survival of neural crest cells. Neural crest cells and mesodermal cells interact during their migration to form head and heart structures. While mesodermal cells are not directly effected by change in Gbx2 expression, neural crest cells are effected and will alter the communication with mesodermal cells, leading to changes in mesoderm derived structures (e.g., muscles). This project aims to understand how Gbx2 guides neural crest development, and how changes in Gbx2 expression influences head (muscle, cartilage, bone, cranial nerve) and heart development. Traditionally the fields of comparative, developmental and evolutionary biology have been unsuccessful in recruiting students and scientists of diverse backrounds. This project will promote collaborations between researchers from non-traditional backgrounds in these areas of biology and historically black universities, Howard University and University of the District of Columbia. This award is funded by the NSF Excellence in Research Program.Technical paragraphCranial neural crest cells (CNCCs) are involved in the development of cranial ganglia, cranial nerves, cranium, connective tissue of head muscles, heart septation, pharyngeal arch artery development, etc. The gastrulation-brain-homeobox (Gbx) transcription factor family member, Gbx2, regulates diverse developmental processes, including anteroposterior patterning within the anterior hindbrain and migration and survival of CNCCs. Since CNCCs are involved in many different developmental processes during head and heart development, this project aims to analyze target genes under direct control of Gbx2, that regulate migration and survival of CNCCs in homozygous Gbx2neo embryos. Furthermore, this project will include analyses of the impact of changes of Gbx2 expression on the morphogenesis of the neural system, and craniofacial and cardiovascular structures. The latter part is of significance as neural crest cells influence the development and differentiation of surrounding tissues and vice versa. During head and haert development the interaction of CNCCs and mesoderm is of particular interest for this project because the mesodermal progenitor cells for most of the head and heart musculature derives from a common progenitor field, called the cardiopharyngeal field. In case Gbx2 is somehow involved in the gene regulatory network underlying the differentiation of that mesodermal progenitor field, directly via altering the transcription of genes or indirectly via altering the neural crest - mesodermal interaction during development, this project will lead to insights into mechanisms regulating head and heart development as well as cranial ganglia and nerve development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.