A loss-of-function mutation in RORB disrupts saltatorial locomotion in rabbits.

Miguel Carneiro,Jennifer Vieillard,Pedro J Esteves,João Branco,Samuel Boucher,José A Blanco-Aguiar,Nuno Santos,Nuno Ferrand,Klas Kullander,Leif Andersson,Sandra Afonso,Pedro Andrade

doi:10.1371/journal.pgen.1009429

Abstract

Saltatorial locomotion is a type of hopping gait that in mammals can be found in rabbits, hares, kangaroos, and some species of rodents. The molecular mechanisms that control and fine-tune the formation of this type of gait are unknown. Here, we take advantage of one strain of domesticated rabbits, the sauteur d'Alfort, that exhibits an abnormal locomotion behavior defined by the loss of the typical jumping that characterizes wild-type rabbits. Strikingly, individuals from this strain frequently adopt a bipedal gait using their front legs. Using a combination of experimental crosses and whole genome sequencing, we show that a single locus containing the RAR related orphan receptor B gene (RORB) explains the atypical gait of these rabbits. We found that a splice-site mutation in an evolutionary conserved site of RORB results in several aberrant transcript isoforms incorporating intronic sequence. This mutation leads to a drastic reduction of RORB-positive neurons in the spinal cord, as well as defects in differentiation of populations of spinal cord interneurons. Our results show that RORB function is required for the performance of saltatorial locomotion in rabbits.

Highlights

The development of coordinated limbed locomotion is an important life-history trait that is key for individual survival and reproduction
We have characterized a recessive mutation present in a specific strain of domestic rabbits that disrupts the jumping gait. The mutation causing this defect in locomotion pattern occurs in the gene coding for the transcription factor receptor B gene (RORB) that is normally expressed in many regions of the nervous system especially in the spinal cord dorsal horn
Our results show that expression of RORB is drastically reduced in the spinal

Summary

Introduction

The development of coordinated limbed locomotion is an important life-history trait that is key for individual survival and reproduction. The interlimb coordination pattern used by animals during locomotion is called gait, which results from an accurate integration of sensory information and motor commands [1,2]. This integration is responsible for determining rhythm, flexor–extensor muscle activity within a limb, and left–right limb coordination, and is largely controlled by central pattern generator (CPG) neural networks located within the spinal cord [3,4,5,6]. Gait pattern differs considerably between species, ranging from bipedal to quadrupedal, and from left-right alternation observed in most mammals to left-right synchronous that allows hopping gaits in kangaroos, most lagomorphs, and some rodents [7]. Despite intense interest in the biomechanical, morphological, and physiological adaptations that characterize distinct types of locomotion in vertebrates [8], the genetic, molecular, and developmental bases underlying differences between individuals and species have seldom been reported [6,9,10,11,12]

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