Alx1 Deficient Mice Recapitulate Craniofacial Phenotype and Reveal Developmental Basis of ALX1-Related Frontonasal Dysplasia.
Alx1 Deficient Mice Recapitulate Craniofacial Phenotype and Reveal Developmental Basis of ALX1-Related Frontonasal Dysplasia.
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DOI：
10.3389/fcell.2022.777887
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发表时间：
2022
影响因子：
5.5
通讯作者：
Jiang R
中科院分区：
文献类型：
--
作者：
Iyyanar PPR;Wu Z;Lan Y;Hu YC;Jiang R
ALX1功能缺失会导致额鼻发育不良综合征FND3，其特征为严重的面部裂隙和小眼畸形。虽然实验室小鼠一直是研究人类颅面出生缺陷发育机制的重要动物模型，但ALX1在小鼠额鼻发育中的作用尚未得到很好的阐释，因为之前报道的唯一一种Alx1突变小鼠品系由于依赖遗传背景的颅神经管闭合失败而表现为无颅畸形。利用CRISPR/Cas9介导的基因组编辑技术，我们构建了一种Alx1缺失小鼠模型，该模型重现了FND颅面畸形，包括正中面裂以及眼和鼻翼发育的中断。原位杂交分析表明，Alx1在产生眼周和额鼻间充质的额鼻神经嵴细胞中强烈表达。Alx1 del/del胚胎表现出眼周间充质细胞凋亡增加，眼周间充质中眼部发育调节因子Pitx2和Lmxb1的表达降低，进而导致视柄形态发生缺陷。此外，Alx1 del/del胚胎表现出额鼻间充质特性的破坏，Pax7表达缺失，同时在发育中的外侧鼻突中出现颌间充质调节因子Lhx6和Lhx8的异位表达。ALX1在额鼻间充质模式形成中的功能部分由ALX4所补充，ALX4是一种同源的ALX家族转录因子，其功能缺失会导致一种较轻微且独特的FND。总之，这些数据揭示了ALX1在眼周间充质发育和额鼻间充质模式形成中先前未知的作用，为ALX1相关FND的致病机制提供了新的见解。
Loss of ALX1 function causes the frontonasal dysplasia syndrome FND3, characterized by severe facial clefting and microphthalmia. Whereas the laboratory mouse has been the preeminent animal model for studying developmental mechanisms of human craniofacial birth defects, the roles of ALX1 in mouse frontonasal development have not been well characterized because the only previously reported Alx1 mutant mouse line exhibited acrania due to a genetic background-dependent failure of cranial neural tube closure. Using CRISPR/Cas9-mediated genome editing, we have generated an Alx1-deletion mouse model that recapitulates the FND craniofacial malformations, including median orofacial clefting and disruption of development of the eyes and alae nasi. In situ hybridization analysis showed that Alx1 is strongly expressed in frontonasal neural crest cells that give rise to periocular and frontonasal mesenchyme. Alx1 del/del embryos exhibited increased apoptosis of periocular mesenchyme and decreased expression of ocular developmental regulators Pitx2 and Lmxb1 in the periocular mesenchyme, followed by defective optic stalk morphogenesis. Moreover, Alx1 del/del embryos exhibited disruption of frontonasal mesenchyme identity, with loss of expression of Pax7 and concomitant ectopic expression of the jaw mesenchyme regulators Lhx6 and Lhx8 in the developing lateral nasal processes. The function of ALX1 in patterning the frontonasal mesenchyme is partly complemented by ALX4, a paralogous ALX family transcription factor whose loss-of-function causes a milder and distinctive FND. Together, these data uncover previously unknown roles of ALX1 in periocular mesenchyme development and frontonasal mesenchyme patterning, providing novel insights into the pathogenic mechanisms of ALX1-related FND.
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ALX4的新等位基因导致小鼠的FGF10表达和眼睑融合的失败。
影响因子：
2.5
作者：
Curtain, Michelle;Heffner, Caleb S.;Maddox, Dennis M.;Gudis, Polyxeni;Donahue, Leah Rae;Murray, Stephen A.
通讯作者：
Murray, Stephen A.
影响因子：
3.5
作者：
Cesario, Jeffry M.;Malt, Andre Landin;Jeong, Juhee
通讯作者：
Jeong, Juhee
影响因子：
2.7
作者：
Denaxa, Myrto;Sharpe, Paul T.;Pachnis, Vassilis
通讯作者：
Pachnis, Vassilis
影响因子：
2.7
作者：
Baek JA;Lan Y;Liu H;Maltby KM;Mishina Y;Jiang R
通讯作者：
Jiang R
影响因子：
2.4
作者：
O'Rahilly, Ronan;Mueller, Fabiola
通讯作者：
Mueller, Fabiola