Making a head: connecting reciprocal signaling to cell reprogramming

脊椎动物的头部有一个惊人的能力，以适应栖息地和生态位的功能要求。其中的核心是颅神经嵴细胞（CNC），它是头部最可变结构的关键贡献者：面骨，软骨和牙齿。少数进化上保守的、非粘附性使用的细胞外信号传导途径控制着大多数面部结构的发育。同样的途径也是面部形状变化的主要贡献者。这是如何实现的？在这项研究计划中，我们将研究CNCs的分化如何受到骨形态发生蛋白（BMPs）的控制，BMPs是一个进化保守的分泌信号分子家族，以及细胞内表观遗传重编程（以ANKRD 11为代表）如何允许在整个发育过程中重复使用这些BMPs。我们专注于结构与主要数控贡献，牙齿和软骨的下颌骨和颅底。 主题1：牙齿矿化。牙齿是研究上皮-间充质串扰的极好模型，其涉及形成釉质的成釉细胞（口腔上皮）和形成牙本质的成牙本质细胞（CNC衍生的间充质）。虽然牙齿硬组织的形成是非常坚固的，但它同时是灵活的，允许广泛的牙齿多样性和功能。在这里，我们将研究ANKRD 11如何程序的矿物质分泌的成牙细胞和成釉细胞，以及如何启动牙齿矿化的时间是由BMP 6/BMP 7控制。 主题2：Meckel软骨的生长和成熟。下颌骨（下颌骨）围绕称为Meckel软骨（MC）的瞬时胚胎软骨形成。MC控制下颌骨的形状和大小。Bmp 7和Ankrd 11的缺失都会导致下颌骨发育迟缓。使用在体内和体外的方法，我们将调查MC分化的顺序步骤，使用CNC或软骨特异性删除这些基因来解开这个关键的胚胎结构的生长和成熟的详细分子调控。主题3：颅底骨生长。颅底（CB）形成颅骨的下部，不可见的部分是头部形状变化的主要贡献者。CB由软骨模板形成，软骨模板通过称为软骨内骨化的过程骨化。Bmp 2、Bmp 7和Ankrd 11的缺失都影响CB的生长和骨化。在这里，我们将探讨细胞外信号和细胞内在的表观遗传重编程如何控制软骨内骨化的过程中，通过比较表型研究与NC或软骨特异性缺失Bmp 2，Bmp 7和Ankrd 11的胚胎。 意义和影响：使用三个明确的颅面结构并行的细胞外信号传导和细胞内重编程的调查将提供独特的见解，了解细胞命运的决定是如何控制和供奉在这些面部结构的发展。这些见解将有助于理解颅面发育的稳健性和可塑性。

The vertebrate head has an amazing capacity to adapt to functional requirements of habitats and ecological niches. Central to this are cranial neural crest cells (CNC), which are key contributors to the most variable structures of the head: the facial bones, cartilages, and teeth. A handful of evolutionary conserved, reiteratively used, extracellular signaling pathways control development of most facial structures. The same pathways are also major contributors to facial shape variation. How is this achieved? In this research program, we will investigate how differentiation of CNCs is controlled by Bone Morphogenetic Proteins (BMPs), a family of evolutionary conserved, secreted signaling molecules, and how intracellular epigenetic reprogramming (represented by ANKRD11) allows the reiterated use of these BMPs throughout development. We focus on structures with major CNC contribution, teeth and cartilages of the mandible and cranial base. Topic 1:  Tooth mineralization. Teeth are an excellent model to study epithelial-mesenchymal crosstalk involving enamel-forming ameloblasts (oral epithelium) and dentin-forming odontoblasts (CNC-derived mesenchyme). While dental hard tissue formation is remarkably robust, it is at the same time flexible, allowing for wide dental diversity and functionality. Here, we will investigate how ANKRD11 programs mineral-secreting odonto- and ameloblasts and how timing of initiation of tooth mineralization is controlled by BMP6/BMP7. Topic 2: Growth and maturation of Meckel's cartilage. The lower jaw (mandible) forms around a transient embryonic cartilage termed Meckel's cartilage (MC). MC controls mandible shape and size. Loss of Bmp7 and Ankrd11 both lead to stunted growth of the mandible. Using in vivo and in vitro approaches, we will investigate the sequential steps of MC differentiation using CNC- or cartilage-specific deletion of these genes to unravel the detailed molecular regulation of growth and maturation of this critical embryonic structure. Topic 3:Bone growth at the cranial base. The cranial base (CB) forming the lower, invisible part of the skull is a major contributor to head shape variation. The CB forms from cartilage templates that ossify through a process called endochondral ossification. Loss of Bmp2, Bmp7 and Ankrd11 all affect CB growth and ossification. Here, we will investigate how extracellular signals and cell-intrinsic epigenetic reprogramming control the process of endochondral ossification through comparative phenotypic studies on embryos with NC- or cartilage-specific deletion of Bmp2, Bmp7, and Ankrd11. Significance and impact: The investigation of extracellular signaling and intracellular reprogramming in parallel using three well-defined craniofacial structures will offer unique insight into how cell fate decisions are controlled and enshrined during development of these facial structures. These insights will help understanding the robust yet plastic nature of craniofacial development.