Abstract
The genetic mechanisms underlying the developmental and functional specification of brainstem projection neurons are poorly understood. Here, we use transgenic mouse tools to investigate the role of the gene Hoxb1 in the developmental patterning of vestibular projection neurons, with particular focus on the lateral vestibulospinal tract (LVST). The LVST is the principal pathway that conveys vestibular information to limb-related spinal motor circuits and arose early during vertebrate evolution. We show that the segmental hindbrain expression domain uniquely defined by the rhombomere 4 (r4) Hoxb1 enhancer is the origin of essentially all LVST neurons, but also gives rise to subpopulations of contralateral medial vestibulospinal tract (cMVST) neurons, vestibulo-ocular neurons, and reticulospinal (RS) neurons. In newborn mice homozygous for a Hoxb1-null mutation, the r4-derived LVST and cMVST subpopulations fail to form and the r4-derived RS neurons are depleted. Several general motor skills appear unimpaired, but hindlimb vestibulospinal reflexes, which are mediated by the LVST, are greatly reduced. This functional deficit recovers, however, during the second postnatal week, indicating a substantial compensation for the missing LVST. Despite the compensatory plasticity in balance, adult Hoxb1-null mice exhibit other behavioral deficits that manifest particularly in proprioception and interlimb coordination during locomotor tasks. Our results provide a comprehensive account of the developmental role of Hoxb1 in patterning the vestibular system and evidence for a remarkable developmental plasticity in the descending control of reflex limb movements. They also suggest an involvement of the lateral vestibulospinal tract in proprioception and in ensuring limb alternation generated by locomotor circuitry.
Highlights
The vestibular system appeared early during vertebrate brain evolution, and connections from the vestibular nuclei to motoneurons in the brainstem and spinal cord are highly conserved within the vertebrate radiation (Díaz and Glover, 2002; Beisel et al, 2005; Duncan and Fritzsch, 2012; Straka et al, 2014)
We show that the segmental hindbrain expression domain uniquely defined by the rhombomere 4 (r4) Hoxb1 enhancer is the origin of essentially all lateral vestibulospinal tract (LVST) neurons, and gives rise to subpopulations of contralateral medial vestibulospinal tract neurons, vestibulo-ocular neurons, and reticulospinal (RS) neurons
General summary Using a combination of retrograde labeling and genetic fate mapping, we here provide an extensive characterization of the contribution of r4 to the vestibular system, and in particular to specific populations of vestibular projection neurons
Summary
The vestibular system appeared early during vertebrate brain evolution, and connections from the vestibular nuclei to motoneurons in the brainstem and spinal cord are highly conserved within the vertebrate radiation (Díaz and Glover, 2002; Beisel et al, 2005; Duncan and Fritzsch, 2012; Straka et al, 2014). Vestibular projections appear early during brain development and are patterned by highly stereotyped blueprints of gene expression (Glover and Petursdottir, 1991; Díaz et al, 1998; Glover, 2000, 2003; Pasqualetti et al, 2007; Straka and Baker, 2013). Principal vestibular descending projections include the separate ipsilateral medial vestibulospinal tract (iMVST) and contralateral medial vestibulospinal tract (cMVST), and the strictly ipsilateral lateral vestibulospinal tract (LVST; Glover and Petursdottir, 1988; Díaz et al, 2003; Pasqualetti et al, 2007). A principal function is the activation of limb extensors and deactivation of limb flexors, asymmetrically around the body axis, to generate limb movements that maintain an Received August 21, 2015; accepted November 12, 2015; First published November 24, 2015. 1The authors declare no competing financial interests. 2M.D.B., J.-L.B., W.K., M.S., and J.C.G. designed research; M.D.B., J.-L.B., W.K., E.S., M.S., and J.C.G. performed research; M.D.B., J.-L.B., W.K., M.S., and J.C.G. analyzed data; M.D.B., M.S., and J.C.G. wrote the paper
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