MAMMALIAN DEVELOPMENTAL GENETICS AND ANIMAL MODELS OF HUMAN DISEASES

转基因监管组同时处理#年的项目。 小鼠发育遗传学领域和人类的小鼠模型 疾病。 我们的发育研究已经解决了两只小鼠的功能 LIM同源框基因Lhx3和Lhx4在垂体器官发生中的作用一开始 Lhx3和Lhx4的表达与Rathke病的形成相吻合 脑袋，脑下垂体的原基。我们对老鼠的研究 缺乏Lhx3和/或Lhx4功能的胚胎已经表明 器官是以循序渐进的方式形成的。这两个基因在体内都是冗余的 形成一个明确的袋子。此后，Lhx3控制一个 脑下垂体命运承诺的关键一步。后来，Lhx3和Lhx4 调节垂体特异性细胞的增殖和分化 血统。因此，Lhx3和Lhx4通过 在器官发生的多个阶段控制发育决定。 Sonic Hedgehog(Shh)基因在Sonic Hedgehog(Shh)的模式形成中起关键作用 脊椎动物胚胎组织。我们继续我们对Shh的研究 检测四肢Shh功能的敲除胚胎 并发现该基因对儿童的生长发育是必不可少的 远端肢体结构。此外，该基因还需要 四肢的前后方花纹。我们知道这一点是因为嫁接 Shh突变的间充质酶不能诱导构图活性。这个 Shh突变肢体缺乏Fgf4和5‘Hox-d基因表达 与Shh通过以下方式调节肢体模式的概念一致 基因。 已经开发出了用于肿瘤抑制和治疗的动物模型 先天性巨结肠。(1)在肿瘤抑制模型中，我们检查了 表达不同病毒簇的转基因小鼠的晶状体 癌基因和肿瘤抑制基因Rb和P53。肿瘤抑制因子是 能够控制病毒致癌基因在这个模型中的作用。然而， 过度抑制会导致细胞死亡。我们的结果鼓励人们尝试 通过联合用药来抵消癌基因的有害作用 旨在抑制细胞增殖和促进细胞生长的措施 细胞凋亡。(2)我们最近对携带零突变的小鼠的观察 在编码胶质细胞源性神经营养因子(GDNF)的基因中 为先天性巨结肠的发病机制提供了新的线索。它 似乎肠道神经元的部分丧失足以导致生命 我国GDNF人群中肠蠕动功能障碍的威胁 突变的小鼠。

The Section on Transgene Regulation works simultaneously on projects in the field of mouse developmental genetics and on mouse models of human diseases. Our developmental studies have addressed the function of two mouse LIM-homeobox genes, Lhx3 and Lhx4, in pituitary organogenesis. The onset of Lhx3 and Lhx4 expression coincides with the formation of Rathke's pouch, the primordium of the pituitary gland. Our studies of mouse embryos that lack the function of Lhx3, Lhx4, or both, have shown that the organ forms in a stepwise fashion. Both genes act redundantly during the formation of a definitive pouch. Thereafter, Lhx3 controls a critical step of pituitary fate commitment. Later, Lhx3 as well as Lhx4 regulate the proliferation and differentiation of pituitary-specific cell lineages. Thus, Lhx3 and Lhx4 dictate pituitary organ identity by controlling developmental decisions at multiple stages of organogenesis. The sonic hedgehog (Shh) gene plays a critical role in patterning of vertebrate embryonic tissues. We have continued our study of the Shh knockout embryo with an examination of Shh function during limb development and find that the gene is essential for the outgrowth of distal limb structures. In addition, the gene is required for anterior-posterior patterning of the limbs. We know this because grafts of Shh mutant mesenchyme are unable to induce patterning activity. The absence of Fgf4 and 5'Hox-d gene expression in Shh mutant limbs is consistent with the notion that Shh regulates limb patterning via these genes. Animal models have been developed for tumor suppression and for Hirschsprung's disease. (1) In the tumor suppression model, we examined lenses of transgenic mice that express different constellations of viral oncogenes and the tumor suppressors RB and p53. Tumor suppressors are able to control the action of viral oncogenes in this model. However, excess suppression can cause cell death. Our results encourage attempts to counteract the deleterious function of oncogenes by a combination of measures aimed at decreasing cell proliferation and enhancing cell apoptosis. (2) Our recent observations of mice that carry a null mutation in the gene encoding glial cell line derived neurotrophic factor (GDNF) have shed new light on the pathogenesis of Hirschsprung's disease. It appears that partial loss of enteric neurons is sufficient to cause life threatening dysfunction of gut peristalsis among our population of GDNF mutant mice.