Cell Fate Determination in Fetal Testes

对发育、生殖和干生物学的一个主要兴趣是： 前体细胞获得分化为各种特殊细胞类型的指令 器官。了解细胞命运如何决定不仅满足了人们的好奇心 组织如何形成，而且对控制和操纵也有很大影响 用于组织再生和治疗目的的分化程序。主要 该提案的目标是了解胎儿和成人 Leydig 细胞谱系如何 负责男性男性化和生育能力的细胞类型是 成立。胎儿和成人间质细胞是两种不同的产生雄激素的细胞 出现在不同的发育阶段并表现出独特的形态和 分子特征。胎儿和成人间质细胞建立缺陷 人口或其产生激素的能力对 男性生殖道的分化、精子发生和生育力。因此是 对于理解这两个间质细胞群体如何产生及其它们的产生至关重要 差异化受到监管。我们的初步结果表明，胎儿和成人 Leydig 细胞起源于胎儿生命中的共同前体和刺猬 (Hh) 信号传导 途径负责将这两个 Leydig 细胞谱系与 共同的前体种群。因此，我们建议 1) 调查以下因素的影响： 胎儿和成人 Leydig 细胞分化过程中 Hh 的异位激活，2) 分离 假定的 Leydig 细胞前体并检查它们分化为成体的能力 Leydig 细胞，3) 检查 Gli1 阳性间质细胞对成体的贡献 间质细胞。该应用不仅将提供对生物基础的深入了解 睾丸中的细胞命运决定，但通过识别也具有临床意义 易受男性性发育障碍影响的过程。

A central interest in developmental, reproductive, and stem biology is how common precursor cells acquire instruction to differentiate into specialized cell types in various organs. Understanding how cell fates are determined not only satisfies the curiosity on how tissues form, but also has a great implication in controlling and manipulating the differentiation program for tissue regeneration and therapeutical purposes. The main goal of this proposal is to understand how fetal and adult Leydig cell lineages, the cell types responsible for masculinization and fertility of the male, are established. Fetal and adult Leydig celis are two distinct androgen-producing celis that appear at different developmental stages and exhibit unique morphological and molecular characteristics. Defects in the establishment of fetal and adult Leydig cell populations or their ability to produce hormones have a profound impact on differentiation of male reproductive tract, spermatogenesis, and fertility. It is therefore essential to understand how these two Leydig celi populations arise and their differentiation is regulated. Our preliminary results suggest that fetal and adult Leydig cells originate from a common precursor in fetal life and the hedgehog (Hh) signaling pathway is responsible for the separation of these two Leydig celi lineages from the common precursor population. We therefore propose to 1) investigate the effects of ectopic activation of the Hh in the differentiation of fetal and adult Leydig cells, 2) isolate the putative Leydig cell precursors and examine their ability to differentiate into adult Leydig cells, and 3) examine the contribution of Gli1-positive interstitial cells to adult Leydig cells. This application will not only provide an insight into the biological basis of cell fate determination in testes, but will also have clinical relevance by identifying processes susceptible to disorders of male sexual development.