Molecular mechanisms of limb regeneration: insights from regenerating legs of the cricket Gryllus bimaculatus

Abstract

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.

Intrinsic Disorder in Tetratricopeptide Repeat Proteins

“…Some TPR proteins might act as chaperones (e.g., the members of the UCS (UNC-45/CRO1/She4p) family of proteins are specific chaperones for the folding, assembly, and function of myosin [79]). Among various biological functions ascribed to the TPR proteins are: control of proteins responsible for organization and homeostasis of the endoplasmic reticulum [80]; regulation of the biosynthesis of the photosynthetic apparatus via involvement in almost all of the steps crucial for biogenesis of the thylakoid membranes [81]; assistance in the de novo assembly and stability of a multi-component pigment-protein complex, photosystem II (PSII) [82]; the quality control of secretory and membrane proteins mislocalized to the cytosol [83]; control of limb regeneration in crickets [84] and plastid protein import [85]. Also, in biotechnology, because of their binding versatility and designability, TPR repeats are used for the creation of repeat protein scaffolds serving as a basis of the biomolecular templating of functional hybrid nanostructures [86,87].…”

Reflections on Bateson's rule: Solving an old riddle about why extra legs are mirror‐symmetric

“…Dpp, decapentaplegic; Wg, wingless HELD AND SESSIONS | 227 Shelton, 1981)) assuming, of course, that they utilize Dpp and Wg in roughly the same way as flies do. That assumption has been verified in crickets (Bando et al, 2018).…”

Evolution of Regeneration in Animals: A Tangled Story

“…In planarians, the formation of blastema results from the proliferation of neoblasts in response to amputation (Bertemes et al, 2020); in crustaceans and insects, wound blastema is formed from the migrating epidermal cells that undergo dedifferentiation (Mito et al, 2002;Das, 2015;Bando et al, 2018).…”