Department of Genetics, Case Western Reserve University, Cleveland, OH, USA.
Adv Exp Med Biol. 2009;668:105-15. doi: 10.1007/978-1-4419-1664-8_11.
To investigate the physiological role of menin, the protein product of the MEN1 gene, several groups have utilized gene targeting strategies to delete one or both copies of the mouse homolog Men1. Mice that are homozygous null for Men1 die during embryogenesis. Heterozygous Men1 mice are viable and develop many of the same types of tumors as humans with MEN1. In addition to conventional knockouts of Men1, tissue-specific elimination of menin using cre-lox has been achieved in pancreatic beta cells, anterior pituitary, parathyroid, liver, neural crest and bone marrow, with varying results that are dependent on cell context. In this chapter, we compare the phenotypes of the different conventional Men1 knockouts, detail the similarities and differences between Men1 pathogenesis in mice and humans and highlight results from recent crossbreeding studies between Men1 mutants and mice with null mutations in genes within the retinoblastoma pathway, including p18(Inc4c), p27(Kip1) and Rb. In addition, we discuss not only how the Men1 mutants have shed light on the role of menin in endocrine tumor suppression, but also how Men1 mutant mice have helped uncover previously unrecognized roles for menin in development, leukemogenesis and gestational diabetes.
为了研究 MEN1 基因产物 menin 的生理作用，几个研究小组利用基因靶向策略敲除了小鼠同源物 Men1 的一个或两个拷贝。纯合子 Men1 缺失的小鼠在胚胎发育过程中死亡。杂合子 Men1 小鼠是存活的，并发展出与 MEN1 患者相同类型的许多肿瘤。除了常规的 Men1 敲除外，还使用 cre-lox 在胰腺β细胞、垂体前叶、甲状旁腺、肝脏、神经嵴和骨髓中实现了 menin 的组织特异性消除，其结果因细胞背景而异。在本章中，我们比较了不同常规 Men1 敲除的表型，详细描述了小鼠和人类 Men1 发病机制之间的相似性和差异，并强调了 Men1 突变体与视黄醇途径中基因（包括 p18(Inc4c)、p27(Kip1)和 Rb）的 null 突变小鼠之间最近的杂交研究结果。此外，我们不仅讨论了 Men1 突变体如何阐明 menin 在内分泌肿瘤抑制中的作用，还讨论了 Men1 突变体小鼠如何帮助揭示 menin 在发育、白血病发生和妊娠糖尿病中的先前未被认识的作用。
