Cell Fate Determination in Fetal Testes

对发育、生殖和干细胞生物学的一个主要兴趣是 前体细胞获得分化为各种不同特化细胞类型的指令 器官。了解细胞命运是如何决定的不仅满足了人们对 组织是如何形成的，而且对控制和操纵 用于组织再生和治疗目的的分化计划。主 这项提议的目标是了解胎儿和成人间质细胞系是如何 负责男性阳性化和生育的细胞类型是 已经成立了。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过程中的缺陷 人口或其产生荷尔蒙的能力对 男性生殖道分化、精子发生和生育。因此，它是 对于理解这两个莱迪格细胞种群是如何产生的以及它们的 分化是受调控的。我们的初步结果表明，胎儿和成年Leydig 细胞起源于胎儿生命中的一种共同前体和刺猬(HH)信号 帕奇负责将这两个莱迪格细胞系从 共同的前驱种群。因此，我们建议1)调查 HH在胎儿和成人间质细胞分化中的异位激活，2)分离株 间质细胞前体细胞及其向成体分化能力的检测 间质细胞，以及3)检测Gli1阳性间质细胞对成人的贡献 间质细胞。这一应用不仅将提供对 睾丸细胞命运的决定，但也将有临床意义，通过识别 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.