Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate.
Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate.
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DOI：
10.1371/journal.pone.0120517
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lipinski RJ
中科院分区：
文献类型：
--
作者：
Heyne GW;Melberg CG;Doroodchi P;Parins KF;Kietzman HW;Everson JL;Ansen-Wilson LJ;Lipinski RJ
Hedgehog（Hh）信号通路介导大脑和面部发育的多个时空特异性方面。已知该途径的遗传和化学破坏会导致一系列结构畸形，包括前脑无裂畸形（HPE）、唇裂伴或不伴腭裂（CL/P）和仅继发腭裂（CPO）。在这里，我们研究了由急性，阶段特异性Hh信号抑制引起的畸形模式。定时妊娠的野生型C57 BL/6 J小鼠在妊娠日（GD）7.0和10.0之间的离散时间点施用单剂量的有效途径拮抗剂维莫德吉，所述间隔大约对应于人类妊娠的第15天至第24天。由此产生的面部和大脑畸形的模式是依赖于曝光的阶段。GD7.0和GD8.25之间的损伤导致HPE，在GD7.5暴露后发生率达到峰值。还观察到单侧唇裂延伸至主腭，暴露后的峰值发生率为GD 8.875。GD9.0和GD10.0之间的损伤导致CPO和前肢异常。我们以前已经证明，Hh拮抗剂诱导的唇裂的结果从内侧鼻突的不足，并在这里显示，CPO与上颌衍生的腭架的生长减少。通过定义HPE，CL/P和CPO诱导的关键时期与精细的时间分辨率，这些结果提供了一种机制，Hh通路中断可以导致“非综合征”口面裂，或HPE与或不与共同发生的裂缝。这项研究还建立了一个新的和易于处理的人类颅面畸形的小鼠模型，使用单剂量的市售和途径特异性药物。
The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), and clefts of the secondary palate only (CPO). Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in “non-syndromic” orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.
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影响因子：
3.8
作者：
Lipinski, Robert J.;Hutson, Paul R.;Bushman, Wade
通讯作者：
Bushman, Wade
影响因子：
2.7
作者：
Marcucio, RS;Cordero, DR;Helms, JA
通讯作者：
Helms, JA
DOI：
10.1002/tera.1420160304
发表时间：
1977-01-01
期刊：
TERATOLOGY
影响因子：
--
作者：
MATSUNAGA, E;SHIOTA, K
通讯作者：
SHIOTA, K
影响因子：
4.2
作者：
Lidral, Andrew C;Moreno, Lina M;Bullard, Steven A
通讯作者：
Bullard, Steven A
影响因子：
3.7
作者：
Lipinski RJ;Hammond P;O'Leary-Moore SK;Ament JJ;Pecevich SJ;Jiang Y;Budin F;Parnell SE;Suttie M;Godin EA;Everson JL;Dehart DB;Oguz I;Holloway HT;Styner MA;Johnson GA;Sulik KK
通讯作者：
Sulik KK