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地交织在一起。它们具有相同的分子调控机制和一些祖细胞群。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。中胚层细胞和神经嵴细胞对头颈部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的早期就通过一组特定的基因（指示因子）被指定，然后遵循它们的轨迹成为肌肉、结缔组织等。一个早期的指示因子，原肠胚形成-脑同源盒2 (Gbx2)，对神经嵴细胞的迁移（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。虽然中胚层细胞不直接受到Gbx2表达变化的影响，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（如肌肉）的变化。本项目旨在了解Gbx2如何引导神经嵴发育，以及Gbx2表达变化如何影响头部（肌肉、软骨、骨、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在招收不同背景的学生和科学家方面是不成功的。该项目将促进来自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。颅神经嵴细胞（cncc）参与了颅神经节、颅神经、头盖骨、头肌结缔组织、心隔、咽弓动脉等的发育。原肠胚-脑同源盒（Gbx）转录因子家族成员Gbx2调节多种发育过程，包括前脑后脑内的前后模式和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，本项目旨在分析Gbx2直接控制的靶基因，这些基因在Gbx2neo纯合子胚胎中调控cncc的迁移和存活。此外，本项目将包括分析Gbx2表达变化对神经系统、颅面和心血管结构形态发生的影响。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。在头部和心脏发育过程中，cncc和中胚层的相互作用是本项目特别感兴趣的，因为大多数头部和心脏肌肉组织的中胚层祖细胞来自一个共同的祖细胞场，称为心咽部场。如果Gbx2以某种方式参与了中胚层祖区分化的基因调控网络，直接通过改变基因转录或间接通过改变发育过程中神经嵴-中胚层的相互作用，该项目将有助于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。该奖项反映了美国国家科学基金会的法定使命，并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.