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Abstract：
The generation of therapeutic β-cells from human pluripotent stem cells relies on the identification of growth factors that faithfully mimic pancreatic β-cell development in vitro. In this context, the aim of the study was to determine the expression and function of the glial cell line derived neurotrophic factor receptor alpha 3 (GFRα3) and its ligand artemin (Artn) in islet cell development and function. GFRα3 and Artn expression were characterized by in situ hybridization, immunochemistry, and qRT-PCR. We used GFRα3-deficient mice to study GFRα3 function and generated transgenic mice overexpressing Artn in the embryonic pancreas to study Artn function. We found that GFRα3 is expressed at the surface of a subset of Ngn3-positive endocrine progenitors as well as of embryonic α- and β-cells, while Artn is found in the pancreatic mesenchyme. Adult β-cells lack GFRα3 but α-cells express the receptor. GFRα3 was also found in parasympathetic and sympathetic intra-islet neurons as well as in glial cells in the embryonic and adult pancreas. The loss of GFRα3 or overexpression of Artn has no impact on Ngn3 and islet cell formation and maintenance in the embryo. Islet organization and innervation as well as glucose homeostasis is normal in GFRα3-deficient mice suggesting functional redundancy.
摘要：
从人类多能干细胞产生治疗性β细胞依赖于在体外忠实地模拟胰腺β细胞发育的生长因子的鉴定。在这种情况下，该研究的目的是确定神经胶质细胞系衍生的神经营养因子受体α3（GFRα3）及其配体artemin（Artn）在胰岛细胞发育和功能中的表达和功能。GFRα3和Artn表达通过原位杂交进行表征,免疫化学，和qRT-PCR。我们使用GFRα3缺陷小鼠研究GFRα3功能，并在胚胎胰腺中产生过表达Artn的转基因小鼠，以研究Artn功能。我们发现GFRα3在Ngn3阳性内分泌祖细胞亚群以及胚胎α和β细胞的表面表达，而Artn在胰腺间质中发现。成年β细胞缺乏GFRα3，但α细胞表达该受体。在副交感神经和交感神经胰岛内神经元以及胚胎和成年胰腺的神经胶质细胞中也发现了GFRα3。GFRα3的缺失或Artn的过表达对胚胎中Ngn3和胰岛细胞的形成和维持没有影响。GFRα3缺陷小鼠的胰岛组织和神经支配以及葡萄糖稳态正常，表明功能冗余。
