Abstract
HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from fish fins to tetrapod limbs. Indeed, comparative gene expression analyses led to the suggestion that changes in their regulation might have been essential for the diversification of vertebrates’ appendages. In this review, we highlight three potential modifications in the regulation and function of these genes that may have boosted appendage evolution: (1) the expansion of polyalanine repeats in the HoxA11 and HoxA13 proteins; (2) the origin of +a novel long-non-coding RNA with a possible inhibitory function on HoxA11; and (3) the acquisition of cis-regulatory elements modulating 5’ HoxA transcription. We discuss the relevance of these mechanisms for appendage diversification reviewing the current state of the art and performing additional comparative analyses to characterize, in a phylogenetic framework, HoxA11 and HoxA13 expression, alanine composition within the encoded proteins, long-non-coding RNAs and cis-regulatory elements.
Highlights
The autopod, the multi-fingered extremity located at the end of a hindlimb or forelimb, is a specific characteristic of tetrapods [1,2,3]
Taking into account the conserved hoxa13 expression patterns found distally in developing fish fins, why do they not give rise to autopod-like structures? Information gathered from developmental, phylogenetic and gene function studies suggests that, in the course of evolution, two factors had to meet to allow the formation of an autopod domain, those being the alteration of the proximo-distal patterning leading to the formation of novel distal territories, characterized by a specific transcriptome, that co-occurred with, or was followed by, an increase in the levels of HoxA13 transcripts [8,26]
Given the possible inhibitory effect of HoxA11AS on HoxA11 and what seems to be a tetrapod-specific characteristic of HoxA11AS, we present the hypothesis that the evolutionary origin of HoxA11AS was one of the molecular events that might have contributed to the evolution of the fin/limb morphology
Summary
The autopod, the multi-fingered extremity located at the end of a hindlimb or forelimb, is a specific characteristic of tetrapods [1,2,3]. Information gathered from developmental, phylogenetic and gene function studies suggests that, in the course of evolution, two factors had to meet to allow the formation of an autopod domain, those being the alteration of the proximo-distal patterning leading to the formation of novel distal territories, characterized by a specific transcriptome, that co-occurred with, or was followed by, an increase in the levels of HoxA13 transcripts [8,26]. Regarding the proximo-distal patterning, striking differences have been found in the expression of 5’ HoxA genes in fish and tetrapod models that may underlie an increased endoskeletal complexity throughout fin/limb evolution (Figure 1) This process counts with the combined action of three genes encoding master regulators of transcription: Meis, which seems to be essential for stylopod specification; HoxA11 required for proper zeugopod development; and HoxA13, which contributes. We will explore the evolutionary/developmental relevance of these three mechanisms, reviewing the current state of the art concerning HoxA11 and HoxA13 regulation throughout development in species at different phylogenetic positions and discussing how these developmental regulatory networks may have evolved, being at the core of the morphological diversification found in vertebrate appendages
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