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一个基本问题，即细胞在组织发育过程中如何接收和响应来自周围环境和邻近细胞的信号。作为实现这一目标的努力的一部分，我们研究了生长因子信号和细胞外基质蛋白对注定要采用黑素细胞系的胚胎神经脊细胞进行调节的分子机制。在胚胎中，神经脊细胞构成了一个独特的、瞬时的、多潜能的祖细胞群体，具有很高的迁移能力。这些细胞分化为几个谱系，包括产生色素的黑素细胞、神经元、神经胶质细胞和心脏细胞。神经脊细胞的一个子集，从神经管向背侧向腹侧向腹部和四肢迁移，成为黑素母细胞。反过来，黑素母细胞是祖细胞，后来产生出生后的黑素细胞干细胞和完全成熟的黑素细胞，产生黑色素，并负责动物的色素沉积。我们的短期目标集中在研究：*1.体内黑素母细胞归巢和分化的机制。这一目标将确定黑素母细胞在从神经脊向真皮腹侧区域迁移的过程中对周围环境的反应，以及ILK在这些过程中的作用。*2.黑素生成反应的机制。这个目标将分析由邻近细胞的旁分泌刺激激活的关键黑素细胞功能的分子介体。黑素细胞对细胞间相互作用的反应机制。这个目标将检测黑素细胞对邻近细胞刺激的黑素小体转移的调节。*我们将使用基因工程报告小鼠模型，在该模型中，我们将特异性地灭活黑素母细胞及其后代中的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、分化和对邻近细胞旁分泌刺激的反应能力的贡献。破译控制黑素细胞系细胞对周围环境和邻近细胞产生的旁分泌信号的反应的路径和网络，将为许多基本组织的发育和功能提供关键的洞察力，包括那些来自神经脊细胞的组织。

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.*****