OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR.
OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR.
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DOI：
10.1016/j.ydbio.2020.06.013
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发表时间：
2020-12-01
影响因子：
2.7
通讯作者：
Bardwell, Vivian J.
中科院分区：
文献类型：
--
作者：
Hamline, Michelle Y.;Corcoran, Connie M.;Wamstad, Joseph A.;Miletich, Isabelle;Feng, Jifan;Lohr, Jamie L.;Hemberger, Myriam;Sharpe, Paul T.;Gearhart, Micah D.;Bardwell, Vivian J.
关键词：
BCOR是人类发展的关键调节器。女性BCOR的杂合突变导致X连锁发育障碍眼面心齿综合征（OFCD），男性BCOR的半合子突变导致妊娠死亡。BCOR与Polycomb组蛋白结合形成不同Polycomb抑制复合物1（PRC 1）复合物的一个亚家族，命名为PRC1.1。目前，对各种PRC 1复合物的不同发育作用的理解有限。因此，我们产生了一个条件性外显子9-10敲除Bcor等位基因和一个转基因条件性Bcor表达等位基因，并使用这些来定义Bcor的多种作用，并暗示PRC1.1，在小鼠发育。Bcor杂合子的女性表现出镶嵌表达，由于X-连锁的基因表现出出生后的活力降低，并有OFCD样缺陷。相比之下，Bcor半合子在整个男性胚胎导致胚胎致死E9.5。我们进一步剖析了Bcor的作用，通过使用细胞类型特异性Cre等位基因，重点研究了OFCD中受影响的一些组织。神经嵴细胞Bcor基因突变可导致腭裂、下颌骨和鼓室骨缩短、唾液腺异位和舌肌异常。我们发现，在下颌骨区域的缺陷，而不是在腭本身，导致腭裂。Bcor基因突变导致2/3的并指畸形。Isl 1表达谱系中Bcor的突变导致心脏缺陷，包括持续性动脉干、室间隔缺损和胎儿死亡。Bcor在胚胎外谱系中的突变导致胎盘缺陷和妊娠中期致死性。转基因Bcor亚型A在发育过程中的普遍过度表达导致胚胎缺陷和妊娠中期致死。我们在Bcor突变体中发现的缺陷为了解OFCD综合征的病因以及含Bcor的PRC 1复合物如何在发育中发挥作用提供了线索。
BCOR is a critical regulator of human development. Heterozygous mutations of BCOR in females cause the X-linked developmental disorder Oculofaciocardiodental syndrome (OFCD), and hemizygous mutations of BCOR in males cause gestational lethality. BCOR associates with Polycomb group proteins to form one subfamily of the diverse Polycomb repressive complex 1 (PRC1) complexes, designated PRC1.1. Currently there is limited understanding of differing developmental roles of the various PRC1 complexes. We therefore generated a conditional exon 9–10 knockout Bcor allele and a transgenic conditional Bcor expression allele and used these to define multiple roles of Bcor, and by implication PRC1.1, in mouse development. Females heterozygous for Bcor exhibiting mosaic expression due to the X-linkage of the gene showed reduced postnatal viability and had OFCD-like defects. By contrast, Bcor hemizygosity in the entire male embryo resulted in embryonic lethality by E9.5. We further dissected the roles of Bcor, focusing on some of the tissues affected in OFCD through use of cell type specific Cre alleles. Mutation of Bcor in neural crest cells caused cleft palate, shortening of the mandible and tympanic bone, ectopic salivary glands and abnormal tongue musculature. We found that defects in the mandibular region, rather than in the palate itself, led to palatal clefting. Mutation of Bcor in hindlimb progenitor cells of the lateral mesoderm resulted in 2/3 syndactyly. Mutation of Bcor in Isl1-expressing lineages that contribute to the heart caused defects including persistent truncus arteriosus, ventricular septal defect and fetal lethality. Mutation of Bcor in extraembryonic lineages resulted in placental defects and midgestation lethality. Ubiquitous over expression of transgenic Bcor isoform A during development resulted in embryonic defects and midgestation lethality. The defects we have found in Bcor mutants provide insights into the etiology of the OFCD syndrome and how BCOR-containing PRC1 complexes function in development.
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影响因子：
2.7
作者：
Core, Nathalie;Caubit, Xavier;Fasano, Laurent
通讯作者：
Fasano, Laurent
影响因子：
--
作者：
Astolfi, Annalisa;Melchionda, Fraia;Pession, Andrea
通讯作者：
Pession, Andrea
影响因子：
5.3
作者：
Anderson, JP;Dodou, E;Black, BL
通讯作者：
Black, BL
DOI：
10.1073/pnas.111092198
发表时间：
2001-06-05
影响因子：
11.1
作者：
Bi, WM;Huang, WD;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
4.6
作者：
Corbel, Catherine;Diabangouaya, Patricia;Heard, Edith
通讯作者：
Heard, Edith