Bando Tetsuya, Mito Taro, Hamada Yoshimasa, Ishimaru Yoshiyasu, Noji Sumihare, Ohuchi Hideyo
Department of Cytology and Histology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Int J Dev Biol. 2018;62(6-7-8):559-569. doi: 10.1387/ijdb.180048ho.
This review summarizes recent advances in leg regeneration research, focusing on the cricket Gryllus bimaculatus. Recent studies have revealed molecular mechanisms on blastema formation, establishment of positional information, and epigenetic regulation during leg regeneration. Especially, these studies have provided molecular bases in classical conceptual models such as the polar coordinate model, the intercalation model, the boundary model, the steepness model, etc., which were proposed to interpret regeneration processes of the cockroach legs. When a leg is amputated, a blastema is formed through the activation of the Janus-kinase (Jak)/Signal-Transduction-and-Activator-of-Transcription (STAT) pathway. Subsequently, the Hedgehog/Wingless/Decapentaplegic/Epidermal-growth-factor pathways instruct distalization in the blastema, designated as the molecular boundary model. Downstream targets of this pathway are transcription factors Distal-less (Dll) and dachshund (dac), functioning as key regulators of proximodistal pattern formation. Dll and dac specify the distal and proximal regions in the blastema, respectively, through the regulation of tarsal patterning genes. The expression of leg patterning genes during regeneration may be epigenetically controlled by histone H3K27 methylation via Enhancer-of-zeste and Ubiquitously-transcribed-tetratricopeptide-repeat-gene-X-chromosome. For the molecular mechanism of intercalation of the missing structures between the amputated position and the most distal one, Dachsous/Fat (Ds/Ft) steepness model has been proposed, in which the Ds/Ft pathway maintains positional information and determines leg size through dac expression. This model was theoretically verified to interpret the experimental results obtained with cricket legs. Availability of whole-genome sequence information, regeneration-dependent RNA interference, and genome editing technique will have the cricket be an ideal model system to reveal gene functions in leg regeneration.
本综述总结了腿部再生研究的最新进展，重点关注双斑蟋。最近的研究揭示了腿部再生过程中芽基形成、位置信息确立和表观遗传调控的分子机制。特别是，这些研究为经典概念模型提供了分子基础，如极性坐标模型、嵌入模型、边界模型、梯度模型等，这些模型曾被用于解释蟑螂腿部的再生过程。当腿部被截肢时，通过激活Janus激酶（Jak）/信号转导和转录激活因子（STAT）通路形成芽基。随后，刺猬索尼克/无翅/果蝇Decapentaplegic/表皮生长因子通路指导芽基向远端分化，这被称为分子边界模型。该通路的下游靶点是转录因子Distal-less（Dll）和腊肠基因（dac），它们是近端-远端模式形成的关键调节因子。Dll和dac分别通过调节跗节模式基因来确定芽基中的远端和近端区域。再生过程中腿部模式基因的表达可能通过增强子zeste和X染色体上普遍转录的四肽重复基因介导的组蛋白H3K27甲基化受到表观遗传控制。对于缺失结构在截肢位置和最远端之间的嵌入分子机制，提出了Dachsous/Fat（Ds/Ft）梯度模型，其中Ds/Ft通路通过dac表达维持位置信息并决定腿部大小。该模型在理论上得到验证，可解释双斑蟋腿部的实验结果。全基因组序列信息、依赖再生的RNA干扰和基因组编辑技术的可用性将使双斑蟋成为揭示腿部再生中基因功能的理想模型系统。
