GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

小鼠Lhx（LIM/同源框）基因的功能分析。 该基因家族 编码发育调节因子，在模式中发挥关键作用， 在后生动物发育过程中的形成和细胞特化。 他们的 产品含有两个N-末端富含半胱氨酸的基序，LIM结构域， 和相邻的同源结构域。 我们小组已经开始描述 LIM/同源框基因家族的鼠成员的功能。 消融 小鼠生殖系中的Lhx 2基因已经证明， 眼睛和大脑皮层正常发育所需，以及 也是有效的确定性红细胞生成所必需的。 类似的 方法已经确定Lhx 3基因作为一个功能，必不可少的， 垂体前叶和中叶的发育 腺。 我们最近克隆的一个基因lhx 5， 尤其是在前脑形成的时候。 作为补充， 为了解Lhx基因的功能机制，我们克隆了一个新的基因 编码LBP的肽，其结合Lhx肽的LIM结构域，和 似乎在Lhx功能中起协同作用。 大脑发育过程中对Shh（Sonic Hedgehog）基因的需求 在神经管和体节形成期间。 缺乏功能性 Shh基因表现为小头畸形和严重的神经管缺陷。 中脑 和前脑领域减少，视泡融合在整个 中线形成独眼巨人结构。 因此，Shh具有深刻的 在大脑发育中的作用 此外，Shh消融导致损失 沿着前后轴的底板细胞和巩膜层， 指示在神经管的图案化中需要Shh，以及 体节 人类疾病的动物模型。 我们已经生成了小鼠模型， 来帮助测试新的治疗方法。 (1)癌 细胞在过表达野生型p53的小鼠中通过细胞凋亡被消除， 肿瘤抑制功能。 (2)鞘脂代谢是 在我们的Sandhoff和Tay-Sachs小鼠模型中， 遗传性疾病。 (3)小鼠体内缺乏胰岛素受体导致 类似于胰岛素依赖型糖尿病的代谢紊乱。 (4)多巴胺D3受体基因的功能性切除导致 多动小鼠是治疗干预的潜在靶点 在相应的人类行为障碍中。

Functional analysis of murine Lhx (LIM/homeobox) genes. This gene family encodes regulators of development that play pivotal roles in pattern formation and cell specification during metazoan development. Their products contain two N-terminal cysteine-rich motifs, the LIM domains, and an adjacent homeodomain. Our group has begun to characterize the function of murine members of the LIM/homeobox gene family. Ablation of the Lhx2 gene in the mouse germline has demonstrated that this gene is required for normal development of the eye and the cerebral cortex, and is also necessary for efficient definitive erythropoiesis. A similar approach has identified the Lhx3 gene as a function essential for the development of the anterior and intermediate lobes of the pituitary gland. Lhx5, a gene that we cloned most recently, appears to function prominently during forebrain formation. In a complementary effort to understand the mechanism of Lhx gene function, we cloned a novel gene encoding LBP, a peptide that binds the LIM domains of Lhx peptides and appears to play a synergistic role in Lhx function. Requirement for the Shh (sonic hedgehog) gene during brain development and during neural tube and somite formation. Mice that lack a functional Shh gene display microcephaly and severe neural tube defects. Midbrain and forebrain fields are reduced, and optic vesicles fuse across the midline resulting in a cyclops structure. Thus, Shh has a profound function in brain development. In addition, Shh ablation leads to a loss of floor plate cells and sclerotomes along the anterior-posterior axis, indicating a requirement of Shh in the patterning of the neural tube and the somites. Animal models of human diseases. We have generated mouse models designed to aid in the process of testing novel avenues of therapy. (1) Cancer cells are eliminated by apoptosis in mice that overexpress wild-type p53, a tumor suppressor function. (2) Sphingolipid metabolism is characteristically affected in our mouse models of Sandhoff and Tay-Sachs genetic disorders. (3) Lack of insulin receptors in mice leads to metabolic derangements similar to insulin-dependent diabetes mellitus. (4) Functional ablation of the dopamine D3 receptor gene results in hyperactive mice that are potential targets for therapeutic intervention in corresponding human behavioral disorders.