Szemes Marianna, Greenhough Alexander, Malik Karim
Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Front Mol Neurosci. 2019 Apr 16;12:90. doi: 10.3389/fnmol.2019.00090. eCollection 2019.
The neural crest (NC), which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of NC development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signaling pathways have been characterized, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumorigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the NC. In this "Hypothesis and Theory" article, we utilize the next generation sequencing data from neuroblastoma cells and tumors to evaluate the possible influences of Wnt signaling on NC GRNs and on neuroblastoma cell lineages. We propose that Wnt signaling is a major determinant of regulatory networks that underlie mesenchymal/neural crest cell (NCC)-like cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signaling in driving proneural differentiation programmes along the adrenergic (ADRN) lineage. Elucidation of Signaling Regulatory Networks can augment and complement GRNs in characterizing cell identities, which may in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.
神经嵴（NC）被称为第四胚层，由多能细胞群体组成，这些细胞会分化为多种细胞和组织，包括颅面软骨和骨骼、黑素细胞、肾上腺髓质和外周神经系统。已知这些细胞命运是由在神经嵴发育的各个阶段（如诱导、特化和迁移）起作用的基因调控网络（GRN）决定的。尽管转录因子层级结构及其与形态发生信号通路的一些相互作用已得到表征，但调控发育所需的全部复杂活动仍未明确。这些信号通路的失调可能导致肿瘤发生，如神经母细胞瘤，这是一种常见的致命性胚胎癌，被认为起源于神经嵴的交感肾上腺谱系。在这篇“假说与理论”文章中，我们利用来自神经母细胞瘤细胞和肿瘤的下一代测序数据，评估Wnt信号对神经嵴基因调控网络和神经母细胞瘤细胞谱系的可能影响。我们提出，Wnt信号是通过PRRX1和YAP/TAZ转录因子构成间充质/神经嵴样细胞（NCC）身份基础的调控网络的主要决定因素。此外，Wnt还可能与Hedgehog信号协同作用，驱动沿肾上腺素能（ADRN）谱系的神经前体细胞分化程序。阐明信号调控网络可以在表征细胞身份方面增强和补充基因调控网络，这反过来可能有助于设计针对原发性和复发性神经母细胞瘤的改进疗法。
