Mouse Mutagenesis Identifies Novel Roles for Left-Right Patterning Genes in Pulmonary, Craniofacial, Ocular, and Limb Development
Mouse Mutagenesis Identifies Novel Roles for Left-Right Patterning Genes in Pulmonary, Craniofacial, Ocular, and Limb Development
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DOI：
10.1002/dvdy.21874
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发表时间：
2009-03-01
影响因子：
2.5
通讯作者：
Norris, Dominic P.
中科院分区：
文献类型：
--
作者：
Ermakov, Alexander;Stevens, Jonathan L.;Norris, Dominic P.
脊椎动物器官在位置和图案上表现出一致的左右（L-R）不对称性。为了识别参与这一过程的基因，我们进行了基于 ENU 的遗传筛选。在分析的 135 个品系中，有 11 个显示出影响 L-R 模式的明显单基因缺陷，包括已知 L-R 基因的 3 个新等位基因和新 L-R 位点中的突变体。我们确定了 6 个品系（称为“喘气”），除了异常的 L-R 模式和相关的心血管缺陷外，还具有复杂的表型，包括肺发育不全、脑外畸形、多指畸形、眼部和颅面畸形。这些复杂的异常存在于某些人类疾病综合征中（例如 HYLS、SRPS、VACTERL）。喘息的胚胎也显示出纤毛发生的缺陷，这表明纤毛在这些人类先天畸形综合征中发挥着作用。我们的结果表明，控制纤毛发生和左右不对称的基因除了在心脏模式中的已知作用外，还在肺、颅面、眼和四肢发育中发挥重要和意想不到的作用，对人类先天性畸形综合征有影响。发展动力学 238:581-594, 2009。(C) 2009 Wiley-Liss, Inc.
Vertebrate organs show consistent left-right (L-R) asymmetry in placement and patterning. To identify genes involved in this process we performed an ENU-based genetic screen. Of 135 lines analyzed 11 showed clear single gene defects affecting L-R patterning, including 3 new alleles of known L-R genes and mutants in novel L-R loci. We identified six lines (termed "gasping") that, in addition to abnormal L-R patterning and associated cardiovascular defects, had complex phenotypes including pulmonary agenesis, exencephaly, polydactyly, ocular and craniofacial malformations. These complex abnormalities are present in certain human disease syndromes (e.g., HYLS, SRPS, VACTERL). Gasping embryos also show defects in ciliogenesis, suggesting a role for cilia in these human congenital malformation syndromes. Our results indicate that genes controlling ciliogenesis and left-right asymmetry have, in addition to their known roles in cardiac patterning, major and unexpected roles in pulmonary, craniofacial, ocular and limb development with implications for human congenital malformation syndromes. Developmental Dynamics 238:581-594, 2009. (C) 2009 Wiley-Liss, Inc.