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Abnormal Craniofacial Morphogenesis of the Small Eye Rat

小眼大鼠颅面形态发生异常

基本信息

批准号：
08457475
负责人：
OSUMI Noriko
金额：
$ 4.86万
依托单位：
National Center of Neurologu & Psychiatry (1997-1998)Tokyo Medical and Dental University (1996)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457475/
关键词：
Pax-6 gene Mutant rat Midbrain Crest cells Cell migration Craniofacial abnormality Lewis X Fucosyltransferase LewisX糖鎖 HNK-1 epitope 内田ラット哺乳類全胚培養頭部神経堤細胞運動神経 Islet-2遺伝子体性運動性神経

项目摘要

Craniofacial Morphogenesis of vertebrates includes complex processes such as formation of the neural tube, migration and differentiation of neural crest cells, and development of sensory organs and nervous systems. Any failures in these developmental processes result in various congenital deseases, e.g., excencephaly, cleft lip and palate, micrognathia ; malformed teeth etc. In the present research project, we used a mutant rat strain called Small eye rat (rSey2) as a good model for analyzing craniofacial morpho-genesis in mammals. The Small eye rat has a mutation in Pax6 gene encoding a transcription factor. Pax6 is originally cloned by homology with Drosophila gene called paired. Homozygous new born has no eyes and no nose and exhibit severe craniofacial malformations. We identified that impaired migration of midbrain crest cells into the frontonasal mass leads to dysplasia of nasal cartilage and related facial bones. Pax6 gene expression is absent from the crest cells but positive i … More n the frontonasal epithelium, i.e., the pathway for midbrain crest cells. Normal crest cells isolated fromthe wild-type midbrain failed to migrate into the frontonasal mass in the host mutant embryos. Therefore, Pax6 is suggested to influence the midbrain crest cell migration toward the frontonasal mass in a cell non-autonomous mechanism. We also found that LewisX is distributed in the frontonasal epithelium of the wild type embryos, while it is absent from the mutant epithelium. Instead, the frontonasal epithelium of the mutant expressed HNK-1 epitope, which shares a common precursor with LewisX.Biochemical analyses showed that enzyme activity of fucosyltransferase, which is involved in synthesis of Lewis X, was drastically lower in the homozygotes. Among various genes encoding fucosyltransferases, we identified that expression of FucT IX, a novel fucosyltransferase gene, is specifically lost in the mutant. From these results, Pax6 is suggested to be important in craniofacial morphogenesis through controling migration of midbrain crest cells toward the frontnasal mass. Less

脊椎动物的颅面形态发生包括复杂的过程，如神经管的形成，神经嵴细胞的迁移和分化，以及感觉器官和神经系统的发育。这些发育过程中的任何失败都会导致各种先天性疾病，例如，在目前的研究项目中，我们使用了一个突变的大鼠品系称为小眼大鼠（rSey 2）作为一个很好的模型，用于分析哺乳动物颅面形态发生。小眼鼠Pax 6基因编码转录因子存在突变。Pax 6基因最初是通过与果蝇基因的同源性被克隆出来的，被称为paired。纯合子新生儿没有眼睛和鼻子，并表现出严重的颅面畸形。我们发现中脑嵴细胞迁移到额鼻肿块受损导致鼻软骨和相关面骨发育不良。Pax 6基因在嵴细胞中表达缺失，但在嵴细胞中表达阳性。 ...更多信息在额鼻上皮中，即，中脑嵴细胞的通路从野生型中脑分离的正常嵴细胞不能迁移到宿主突变胚胎的额鼻团块中。因此，Pax 6可能通过细胞非自主机制影响中脑嵴细胞向额鼻块的迁移。我们还发现LewisX分布在野生型胚胎的额鼻上皮中，而突变体上皮中没有。相反，突变体的额鼻上皮表达HNK-1表位，其与LewisX共享一个共同的前体。生化分析表明，参与刘易斯X合成的岩藻糖基转移酶的酶活性在纯合子中显著降低。在编码岩藻糖基转移酶的各种基因中，我们确定了FucT IX（一种新型岩藻糖基转移酶基因）的表达在突变体中特异性丢失。从这些结果表明，Pax 6是重要的颅面形态发生通过控制迁移的中脑嵴细胞向前鼻质量。少