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一种新型突变体——遗传性多发畸形肢体中 Sonic Hedgehog 信号通路的失活与多指（趾）畸形

Inactivation of Sonic Hedgehog Signaling and Polydactyly in Limbs of Hereditary Multiple Malformation, a Novel Type of Mutant.

作者信息

Matsubara Yoshiyuki, Nakano Mikiharu, Kawamura Kazuki, Tsudzuki Masaoki, Funahashi Jun-Ichi, Agata Kiyokazu, Matsuda Yoichi, Kuroiwa Atsushi, Suzuki Takayuki

机构信息

Division of Biological Science, Graduate School of Science, Nagoya University Nagoya, Japan.

Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University Nagoya, Japan.

出版信息

Front Cell Dev Biol. 2016 Dec 27;4:149. doi: 10.3389/fcell.2016.00149. eCollection 2016.

DOI:10.3389/fcell.2016.00149
PMID:28083533
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5187386/
Abstract

Hereditary Multiple Malformation (HMM) is a naturally occurring, autosomal recessive, homozygous lethal mutation found in Japanese quail. Homozygote embryos () show polydactyly similar to and mutants. Here we characterize the molecular profile of the limb bud and identify the cellular mechanisms that cause its polydactyly. The limb bud shows a severe lack of sonic hedgehog (SHH) signaling, and the autopod has 4 to 11 unidentifiable digits with syn-, poly-, and brachydactyly. The Zone of Polarizing Activity (ZPA) of the limb bud does not show polarizing activity regardless of the presence of SHH protein, indicating that either the secretion pathway of SHH is defective or the SHH protein is dysfunctional. Furthermore, mesenchymal cells in the limb bud do not respond to ZPA transplanted from the normal limb bud, suggesting that signal transduction downstream of SHH is also defective. Since primary cilia are present in the limb bud, the causal gene must be different from and . In the limb bud, a high amount of GLI3A protein is expressed and GLI3 protein is localized to the nucleus. Our results suggest that the regulatory mechanism of GLI3 is disorganized in the limb bud.

摘要

遗传性多发畸形（HMM）是在日本鹌鹑中发现的一种自然发生的常染色体隐性纯合致死突变。纯合子胚胎表现出与 和 突变体相似的多指畸形。在这里，我们描述了 肢体芽的分子特征，并确定了导致其多指畸形的细胞机制。 肢体芽显示出严重缺乏音猬因子（SHH）信号，并且手部有4到11个无法识别的指，伴有并指、多指和短指畸形。 肢体芽的极化活性区（ZPA）无论是否存在SHH蛋白都不显示极化活性，这表明要么SHH的分泌途径有缺陷，要么SHH蛋白功能失调。此外， 肢体芽中的间充质细胞对从正常肢体芽移植来的ZPA没有反应，这表明SHH下游的信号转导也有缺陷。由于 肢体芽中存在初级纤毛，致病基因肯定与 和 不同。在 肢体芽中，大量的GLI3A蛋白表达，并且GLI3蛋白定位于细胞核。我们的结果表明， 肢体芽中GLI3的调节机制紊乱。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/eb46c470cc4b/fcell-04-00149-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/72513d947b11/fcell-04-00149-g0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/e85fb5d3103f/fcell-04-00149-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/1e93930c63dc/fcell-04-00149-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/d5d40a995f92/fcell-04-00149-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/eb46c470cc4b/fcell-04-00149-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/72513d947b11/fcell-04-00149-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/1231f193d347/fcell-04-00149-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/ce90af36954d/fcell-04-00149-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/722aee7c827c/fcell-04-00149-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/e85fb5d3103f/fcell-04-00149-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/1e93930c63dc/fcell-04-00149-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/d5d40a995f92/fcell-04-00149-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b05a/5187386/eb46c470cc4b/fcell-04-00149-g0008.jpg

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