The Molecular, Cellular, Developmental Biology and Genetics Graduate Program, University of Minnesota, Minneapolis, MN, 55455, USA; University of Minnesota Medical Scientist Training Program, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, 55455, USA.
Dev Biol. 2020 Dec 1;468(1-2):110-132. doi: 10.1016/j.ydbio.2020.06.013. Epub 2020 Jul 18.
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.
BCOR 是人类发育的关键调节因子。女性中 BCOR 的杂合突变导致 X 连锁发育障碍眼面心齿综合征（OFCD），而男性中 BCOR 的半合子突变导致胚胎致死。BCOR 与多梳蛋白组蛋白形成多样的多梳抑制复合物 1（PRC1）复合物的一个亚家族，称为 PRC1.1。目前对不同 PRC1 复合物的发育作用知之甚少。因此，我们生成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（以及 PRC1.1）在小鼠发育中的多种作用。由于基因的 X 连锁，表现出镶嵌表达的杂合性 Bcor 雌性表现出出生后生存力降低，并具有 OFCD 样缺陷。相比之下，整个雄性胚胎中的 Bcor 半合子导致胚胎致死，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，专注于 OFCD 中受影响的一些组织。神经嵴细胞中 Bcor 的突变导致腭裂、下颌骨和鼓膜缩短、异位唾液腺和异常舌肌。我们发现，下颌区域的缺陷而不是腭本身导致腭裂。侧中胚层的后腿祖细胞中 Bcor 的突变导致 2/3 并指。Isl1 表达谱系中 Bcor 的突变导致心脏缺陷，包括永存动脉干、室间隔缺损和胎儿致死。外胚层谱系中 Bcor 的突变导致胎盘缺陷和妊娠中期致死。在发育过程中广泛表达转基因 Bcor 同工型 A 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 OFCD 综合征的病因学以及含有 BCOR 的 PRC1 复合物在发育中的作用提供了见解。
