HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.
HES1 is a novel downstream modifier of the SHH-GLI3 Axis in the development of preaxial polydactyly.
复制标题
DOI：
10.1371/journal.pgen.1009982
复制
发表时间：
2021-12
期刊：
影响因子：
4.5
通讯作者：
Hilton MJ
中科院分区：
文献类型：
--
作者：
Sharma D;Mirando AJ;Leinroth A;Long JT;Karner CM;Hilton MJ
Sonic Hedgehog/GLI 3信号传导在调节数字中是至关重要的，例如Gli 3缺陷导致多指畸形，Shh缺陷导致数字减少。SHH/GLI 3信号调节控制间充质细胞增殖的细胞周期因子，同时调节Grem 1以协调BMP诱导的软骨形成。SHH/GLI 3信号还协调其他基因的表达，但它们在趾形成中的重要性仍然未知。利用遗传和分子方法，我们确定了HES 1作为SHH/GLI信号传导轴的下游修饰剂，能够诱导Gli 3缺陷型PPD所需的轴前多指（PPD），并能够克服Shh缺陷的数字限制。我们的数据表明，HES 1，一个直接的SHH/GLI信号转导靶点，通过抑制Cdkn 1b诱导间充质细胞增殖，同时抑制软骨形成基因和前足细胞边界调节因子Pax 9。这些发现确立了HES 1作为PPD发展中SHH/GLI 3信号传导的关键下游效应子。Sonic Hedgehog/GLI 3信号传导在调节数字方面至关重要，例如Gli 3缺陷导致额外的数字，Shh缺陷导致数字减少。SHH/GLI 3信号在肢体发育中调节许多对适当的autopod（手/脚）发育至关重要的基因，然而，并非所有的靶基因都对手指形成真正重要。利用遗传和分子方法，我们确定了HES 1作为SHH/GLI信号传导轴的下游修饰剂，能够诱导Gli 3缺陷型PPD所需的轴前多指（PPD），并能够克服Shh缺陷的数字限制。我们进一步提出了一个机制模型，通过该模型，HES 1协调对正确的手指发育重要的基因的表达。这些发现确立了HES 1作为PPD发展中SHH/GLI 3信号传导的关键下游效应子。
Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD. Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in additional digits and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling within the developing limb regulates numerous genes critical for proper autopod (hand/foot) development, however not all target genes are known to be truly important for digit formation. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. We further propose a mechanistic model by which HES1 coordinates the expression of genes important for proper digit development. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.
登录
查看更多内容
影响因子：
--
作者：
Grogan, Shawn P.;Olee, Tsaiwei;Hiraoka, Koji;Lotz, Martin K.
通讯作者：
Lotz, Martin K.
影响因子：
11.8
作者：
Lopez-Rios, Javier;Speziale, Dario;Robay, Dimitri;Scotti, Martina;Osterwalder, Marco;Nusspaumer, Gretel;Galli, Antonella;Hollaender, Georg A.;Kmita, Marie;Zeller, Rolf
通讯作者：
Zeller, Rolf
影响因子：
4.5
作者：
Hirsch N;Eshel R;Bar Yaacov R;Shahar T;Shmulevich F;Dahan I;Levaot N;Kaplan T;Lupiáñez DG;Birnbaum RY
通讯作者：
Birnbaum RY
影响因子：
2.7
作者：
Hill, Patrick;Goetz, Katrin;Ruether, Ulrich
通讯作者：
Ruether, Ulrich
影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL