Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK.
Compr Physiol. 2020 Mar 12;10(2):389-413. doi: 10.1002/cphy.c150043.
The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme. Endocrine cells of the pituitary gland are organized into structural and functional networks that contribute to the coordinated response of endocrine cells to stimuli; these cellular networks are formed during embryonic development and are maintained or may be modified in adulthood, contributing to the plasticity of the gland. Abnormalities in any of the steps of pituitary development may lead to congenital hypopituitarism that includes a spectrum of disorders from isolated to combined hormone deficiencies including syndromic disorders such as septo-optic dysplasia. Over the past decade, the acceleration of next-generation sequencing has allowed for rapid analysis of the patient genome to identify novel mutations and novel candidate genes associated with hypothalmo-pituitary development. Subsequent functional analysis using patient fibroblast cells, and the generation of stem cells derived from patient cells, is fast replacing the need for animal models while providing a more physiologically relevant characterization of novel mutations. Furthermore, CRISPR-Cas9 as the method for gene editing is replacing previous laborious and time-consuming gene editing methods that were commonly used, thus yielding knockout cell lines in a fraction of the time. © 2020 American Physiological Society. Compr Physiol 10:389-413, 2020.
垂体前叶的发育经历了明确的序贯发育步骤，导致形成一个包含五种不同细胞类型分泌六种不同激素的复杂器官。在这个过程中，一连串信号分子和转录因子的时空表达在器官承诺、细胞增殖、模式形成和终末分化中起着至关重要的作用。腺垂体的形态发生和从共同原基中出现不同的细胞类型是由涉及转录因子和信号分子的复杂调控网络控制的，这些转录因子和信号分子既可以是发育中的垂体固有的，也可以是来自腹侧神经胚、口腔外胚层和周围间质的外源性的。垂体内分泌细胞组织成结构和功能网络，有助于内分泌细胞对刺激的协调反应；这些细胞网络在胚胎发育过程中形成，并在成年期得到维持或可能被修饰，为腺体的可塑性做出贡献。垂体发育任何步骤的异常都可能导致先天性垂体功能减退症，包括从孤立激素缺乏到联合激素缺乏的一系列疾病，包括如 septo-optic 发育不良等综合征。在过去的十年中，下一代测序技术的加速使得对患者基因组进行快速分析成为可能，以鉴定与下丘脑-垂体发育相关的新突变和新候选基因。随后使用患者成纤维细胞进行功能分析，以及从患者细胞中产生的干细胞，正在快速取代对动物模型的需求，同时为新突变提供更具生理相关性的特征描述。此外，CRISPR-Cas9 作为基因编辑方法正在取代以前常用的繁琐和耗时的基因编辑方法，从而在一小部分时间内产生基因敲除细胞系。© 2020 美国生理学会。Compr Physiol 10:389-413, 2020.
