与神经发育障碍相关的拷贝数变体(CNV)的特征在于广泛的表型异质性。特别是,在临床诊断为智力障碍(ID)的儿童中发现了一个CNV,导致染色体16p12.1上多个基因的半合子缺失。除了ID,这种缺失的个体表现出各种症状,包括小头畸形,癫痫发作,心脏缺陷,和生长迟缓。此外,患者还表现出严重的颅面异常,比如小颌,耳朵和鼻子的软骨畸形,和面部不对称;然而,在脊椎动物颅面发育的背景下,尚未研究16p12.1区域内基因的功能。患有这种缺失的患者受影响的颅面组织都来自相同的胚胎前体,颅神经嵴,导致一个或多个16p12.1基因可能参与调节神经c细胞(NCC)相关过程的假设。为了检查这一点,我们描述了16p12.1受影响的基因直系同源物的发育作用,polr3e,Mosmo,uqcrc2和cdr2,在脊椎动物模型系统的颅面形态发生过程中,非洲爪狼.虽然目前已知的这些基因的细胞功能是多样的,我们发现它们在神经管上有相似的表达方式,咽弓,以及后来的颅面结构。由于这些基因在NCC所在的咽弓中显示出共表达,我们试图阐明单个基因缺失对颅面发育和NCC迁移的影响.我们发现几个16p12.1基因的减少会显著破坏颅面和软骨的形成,咽弓迁移,以及NCC规范和运动性。因此,我们已经确定,这些基因中的一些通过调节NCC发育过程中的特定过程在脊椎动物颅面模式中起着重要作用,这可能是导致与16p12.1缺失相关的颅面缺损的潜在机制。
Copy number variants (CNVs) associated with neurodevelopmental disorders are characterized by extensive phenotypic heterogeneity. In particular, one CNV was identified in a subset of children clinically diagnosed with intellectual disabilities (ID) that results in a hemizygous deletion of multiple genes at chromosome 16p12.1. In addition to ID, individuals with this deletion display a variety of symptoms including microcephaly, seizures, cardiac defects, and growth retardation. Moreover, patients also manifest severe craniofacial abnormalities, such as micrognathia, cartilage malformation of the ears and nose, and facial asymmetries; however, the function of the genes within the 16p12.1 region have not been studied in the context of vertebrate craniofacial development. The craniofacial tissues affected in patients with this deletion all derive from the same embryonic precursor, the cranial neural crest, leading to the hypothesis that one or more of the 16p12.1 genes may be involved in regulating neural crest cell (NCC)-related processes. To examine this, we characterized the developmental role of the 16p12.1-affected gene orthologs, polr3e, mosmo, uqcrc2, and cdr2, during craniofacial morphogenesis in the vertebrate model system, Xenopus laevis. While the currently-known cellular functions of these genes are diverse, we find that they share similar expression patterns along the neural tube, pharyngeal arches, and later craniofacial structures. As these genes show co-expression in the pharyngeal arches where NCCs reside, we sought to elucidate the effect of individual gene depletion on craniofacial development and NCC migration. We find that reduction of several 16p12.1 genes significantly disrupts craniofacial and cartilage formation, pharyngeal arch migration, as well as NCC specification and motility. Thus, we have determined that some of these genes play an essential role during vertebrate craniofacial patterning by regulating specific processes during NCC development, which may be an underlying mechanism contributing to the craniofacial defects associated with the 16p12.1 deletion.