To the fin and back again: expanding our understanding of congenital limb malformation

Abstract

Fins are not limbs. However, findings from comparative developmental and genetic analyses show that many of the processes essential in establishing a limb are similar for fin formation. Nevertheless, due to their structural differences, fins are not often used as models to understand the causes or potential treatment of limb disorders.Split hand/foot malformation (SHFM) presents with loss or mis-patterning of elements of hands or feet leading to a ‘clefting-like’ phenotype, often with joining of the digits. This rare disorder is genetically and phenotypically heterogeneous, and knowledge of its etiology remains largely incomplete. Recent work by Truong et al. provides new insight into SHFM by identifying new genetic variants within three different families, predicted to cause changes in function of the PRDM1/Blimp1 gene. PRDM1 is a transcription factor known to be essential for early appendage development in both zebrafish and mice. However, PRDM1 action is nuanced, in part due to its multifaceted roles in integrating signaling, transcription and chromatin state. This complicates the functional characterization of variants in this gene that have unknown significance in SHFM patients. Truong et al. demonstrate the utility of the zebrafish fin as an assay to directly address the function of domain-specific mutations in prdm1a by using the ability of the mutant alleles to rescue fin phenotypes caused by loss of Prdm1a function or, in the case of putative dominant variants, to suppress wildtype zebrafish fin development.A fin may not, or more likely will not, have the complete genetic networks underlying limb development and patterning. However, core mechanisms remain active and, at times, latent in fin development, allowing experimental dissection of mechanisms and gene function. Truong et al. harnessed the experimental malleability of zebrafish to isolate pectoral fin cells in early development and detail Prdm1a-dependent regulation of genes. These data establish aspects of the downstream regulatory network of fin development regulated by Prdm1a, providing insight into the broader array of changes involved in the etiology of this disorder.Core mechanisms and common evolutionary foundations allow for the establishment of defined genetic models of limb disorders in zebrafish and, importantly, accessible experimental models to formulate and test hypotheses on how these disease states are attained. Conversely, identification of disease-associating alleles provides insight into molecular action of genes in development and reveals details of the specificity of their regulation. Fin-in-hand, leading towards new discoveries for congenital limb malformations.