Schuchardt A, Srinivas S, Pachnis V, Costantini F
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Oncogene. 1995 Feb 16;10(4):641-9.
The c-ret proto-oncogene encodes a receptor tyrosine kinase that plays important roles in human disease and in normal mammalian development. Mutations in the human RET gene are associated with multiple endocrine neoplasia syndromes and Hirschsprung's disease in humans, while targeted mutagenesis of murine c-ret resulted in severe developmental abnormalities affecting the excretory and peripheral nervous systems. To examine the evolutionary conservation of the ret protein sequence and its developmental expression pattern, we isolated and sequenced cDNA clones of chicken c-ret and examined its expression in chick embryos and adult tissues. The cytoplasmic domains of chicken and human ret were relatively well conserved (91% similar), but the extracellular domains were more divergent (68% similar), although the conservation of cysteine residues in this region suggests a conserved secondary structure. As in mouse and human, chicken c-ret encodes two protein isoforms. The number and sizes of the transcripts were similar to those in human and mouse cells, and during chick embryogenesis, c-ret mRNA was observed in many of the same sites as in the mouse, including the Wolffian duct and ureteric bud, the enteric, dorsal root, sympathetic and facioacoustic ganglia, and the ventral spinal cord. Evolutionary differences in expression were observed in the trigeminal ganglion, the ventral roots of the spinal cord, the mesenchymal cells of the branchial arches and the adult testes. The results are discussed with regard to the role of the ret receptor in normal development and disease.
c-ret原癌基因编码一种受体酪氨酸激酶，该激酶在人类疾病和正常哺乳动物发育中发挥重要作用。人类RET基因的突变与人类的多发性内分泌肿瘤综合征和先天性巨结肠病相关，而小鼠c-ret的靶向诱变导致影响排泄和外周神经系统的严重发育异常。为了研究ret蛋白序列的进化保守性及其发育表达模式，我们分离并测序了鸡c-ret的cDNA克隆，并检测了其在鸡胚和成年组织中的表达。鸡和人类ret的胞质结构域相对保守（相似度为91%），但胞外结构域差异更大（相似度为68%），尽管该区域半胱氨酸残基的保守性表明二级结构保守。与小鼠和人类一样，鸡c-ret编码两种蛋白异构体。转录本的数量和大小与人类和小鼠细胞中的相似，在鸡胚发育过程中，c-ret mRNA在许多与小鼠相同的部位被观察到，包括中肾管和输尿管芽、肠、背根、交感和听面神经节以及腹侧脊髓。在三叉神经节、脊髓腹根、鳃弓间充质细胞和成年睾丸中观察到表达的进化差异。我们将结合ret受体在正常发育和疾病中的作用对结果进行讨论。
