Signalling in melanocyte development and melanogenesis

我的NSERC发现研究计划的长期目标是解决自然科学中的基本问题，即细胞如何在组织发育过程中接收和响应来自周围环境和邻近细胞的信号。作为我们努力实现这一目标的一部分，我们已经研究了胚胎神经嵴细胞的生长因子信号和细胞外基质蛋白参与调制的分子机制，这些细胞注定要采用黑素细胞系。** 在胚胎中，神经嵴细胞构成具有高迁移能力的独特的、瞬时的和多能的祖细胞群体。这些细胞分化成几个谱系，包括产生色素的黑素细胞、神经元、神经胶质细胞和心肌细胞。从神经管向腹侧腹部和四肢迁移的神经嵴细胞亚群成为成黑素细胞。成黑素细胞又是后来产生出生后黑素细胞干细胞和完全成熟的黑素细胞的祖细胞，黑素细胞产生黑色素，并负责动物色素沉着。我们的短期目标是调查：*1。体内黑素细胞归巢及分化的机制。 这一目标将确定成黑素细胞迁移过程中从神经嵴到腹侧区域的真皮，ILK在这些过程中的作用，他们的周围环境的反应。2.黑素生成反应的机制。这一目标将分析分子介质的关键黑素细胞功能激活旁分泌刺激邻近细胞。3.黑素细胞对细胞间相互作用的反应机制。该目标将检查响应于邻近细胞的刺激而从黑素细胞转移黑素体的调节。我们将使用基因工程的报告小鼠模型，其中我们将专门在成黑素细胞及其后代中表达Ilk基因，用于体内谱系追踪研究。我们还将使用原代黑素细胞培养物在细胞和分子水平上鉴定各种信号网络对黑素细胞存活、分化和对来自邻近细胞的旁分泌刺激作出反应的能力的贡献。破译控制黑素细胞谱系细胞对其周围环境和邻近细胞产生的旁分泌信号的反应的途径和网络，将为了解许多基本组织（包括来自神经嵴细胞的组织）的发育和功能所涉及的基本过程提供关键见解。

The long-term goal of my NSERC Discovery research program is to address the fundamental question in the Natural Sciences of how cells receive and respond to signals from their surrounding environment and from neighbouring cells during tissue development. As part of our efforts to fulfill this goal, we have examined molecular mechanisms involved in modulation by growth factor signals and extracellular matrix proteins of embryonic neural crest cells fated to adopt a melanocytic cell lineage. ******In the embryo, neural crest cells constitute a unique, transient and multipotent progenitor cell population with high migratory capacity. These cells differentiate into several lineages, including pigment-producing melanocytes, neurons, glial cells and cardiac cells. A subset of neural crest cells that migrate dorso-laterally from the neural tube towards the ventral abdomen and limbs become melanoblasts. Melanoblasts in turn are progenitor cells that later give rise to postnatal melanocyte stem cells and fully mature melanocytes which produce melanin, and are responsible for animal pigmentation. Our short-term objectives focus on investigating:******1. The mechanisms of melanoblast homing and differentiation in vivo. This objective will determine melanoblast responses to their surrounding environment during migration from the neural crest to ventral regions across the dermis, and the role of ILK in these processes. ******2. The mechanisms of melanogenic responses. This objective will analyze molecular mediators of key melanocyte functions activated by paracrine stimulation from neighbouring cells. ******3. The mechanisms of melanocyte responses to cell-cell interactions. This objective will examine the modulation of melanosome transfer from melanocytes in response to stimuli by neighbouring cells.******We will use genetically engineered reporter mouse models in which we will specifically inactivate the Ilk gene in melanoblasts and their progeny, for lineage-tracing studies in vivo. We will also use primary melanocytic cell cultures to identify at the cellular and molecular level the contribution of various signalling networks to melanocyte survival, differentiation and ability to respond to paracrine stimuli from neighbouring cells. Deciphering the pathways and networks that control responses of melanocytic lineage cells to their surrounding environment and to paracrine signals produced by neighbouring cells will provide key insight into fundamental processes involved in development and function of many essential tissues, including those derived from neural crest cells.*****