Mice with a targeted mutation of Patched2 are viable but develop alopecia and epidermal hyperplasia
Mice with a targeted mutation of Patched2 are viable but develop alopecia and epidermal hyperplasia
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DOI：
10.1128/mcb.00295-06
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发表时间：
2006-09-01
影响因子：
5.3
通讯作者：
Hui, Chi-chung
中科院分区：
文献类型：
--
作者：
Nieuwenhuis, Erica;Motoyama, Jun;Hui, Chi-chung
刺猬（Hh）信号在果蝇和脊椎动物的组织模式和发育中起着关键作用。编码Hh受体的Patched1 （Ptc1）基因在瘤状基底细胞癌综合征中发生突变，瘤状基底细胞癌综合征是一种与发育异常和基底细胞癌（BCC）和髓母细胞瘤（MB）发病率增加相关的人类遗传疾病。Ptc1突变也发生在散发性BCC和MB中。小鼠突变研究证实Ptc1是一种肿瘤抑制因子。我们之前发现了第二个哺乳动物补丁基因Ptc2，并证明了其在胚胎发生过程中的独特表达模式，表明其在发育中具有独特的作用。最值得注意的是，Ptc2在发育中的毛囊表皮区与Shh重叠表达，并在发育中的肢体芽、小脑和睾丸中高度表达。在这里，我们描述了Ptc2（tm1/tm1）小鼠的产生和表型分析。我们的分子分析表明Ptc2（tm1）可能代表一个次胚等位基因。尽管Ptc2在胚胎发育过程中是动态表达的，Ptc2（tm1/tm1）小鼠是活的、可育的，并且明显正常。有趣的是，成年Ptc2（tm1/tm1）雄性动物的皮肤病变包括脱发、溃疡和表皮增生。虽然Ptc1的功能补偿可能解释了Ptc2缺陷小鼠缺乏强突变表型的原因，但我们的研究结果表明，正常的Ptc2功能是成人皮肤稳态所必需的。
Hedgehog (Hh) signaling plays pivotal roles in tissue patterning and development in Drosaphila melanogaster and vertebrates. The Patched1 (Ptc1) gene, encoding the Hh receptor, is mutated in nevoid basal cell carcinoma syndrome, a human genetic disorder associated with developmental abnormalities and increased incidences of basal cell carcinoma (BCC) and medulloblastoma (MB). Ptc1 mutations also occur in sporadic forms of BCC and MB. Mutational studies with mice have verified that Ptc1 is a tumor suppressor. We previously identified a second mammalian Patched gene, Ptc2, and demonstrated its distinct expression pattern during embryogenesis, suggesting a unique role in development. Most notably, Ptc2 is expressed in an overlapping pattern with Shh in the epidermal compartment of developing hair follicles and is highly expressed in the developing limb bud, cerebellum, and testis. Here, we describe the generation and phenotypic analysis of Ptc2(tm1/tm1) mice. Our molecular analysis suggests that Ptc2(tm1) likely represents a hypomorphic allele. Despite the dynamic express ion of Ptc2 during embryogenesis, Ptc2(tm1/tm1) mice are viable, fertile, and apparently normal. Interestingly, adult Ptc2(tm1/tm1) male animals develop skin lesions consisting of alopecia, ulceration, and epidermal hyperplasia. While functional compensation by Ptc1 might account for the lack of a strong mutant phenotype in Ptc2-deficient mice, our results suggest that normal Ptc2 function is required for adult skin homeostasis.