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Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice.

Di Bonito M, Boulland JL, Krezel W, Setti E, Studer M, Glover JC - eNeuro (2015)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biology Valrose, UMR 7277, University of Nice Sophia Antipolis, 06108 Nice, France; Institute of Biology Valrose, INSERM, U1091, 06108 Nice, France; Institute of Biology Valrose, CNRS, UMR 7277, 06108 Nice, France.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus

Effects of Hoxb1- mutation on vestibulo-ocular neuron groups. A–F, No loss of iC-VO or scattered ipsilateral VO neurons in the Hoxb1- mouse. A–C are a series of parasagittal sections in a wild-type (wt) mouse embryo showing the presence of the few iC-VO neurons in r4 and scattered ipsilateral VO neurons in r3. Some of each of these can be seen to be r4-derived (examples are indicated by white arrowheads). D–F are a similar series of sections in the Hoxb1- mutant, in which the situation is similar to that in the wild-type: there is no indication that iC-VO or scattered ipsilateral VO neurons are lost, and some of each are r4-derived. G–L, Ectopic presence of r4-derived neurons in the region containing the iR-VO group. G–L present a series of parasagittal sections through the region containing the iR-VO group in wild-type (G–I) and Hoxb1- (J–L) mice. In this region, Hoxb1- mutants have ectopic r4-derived neurons (examples are indicated by white arrowheads) not seen in wild-type mice. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Scale bar, 200 µm.
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Figure 4: Effects of Hoxb1- mutation on vestibulo-ocular neuron groups. A–F, No loss of iC-VO or scattered ipsilateral VO neurons in the Hoxb1- mouse. A–C are a series of parasagittal sections in a wild-type (wt) mouse embryo showing the presence of the few iC-VO neurons in r4 and scattered ipsilateral VO neurons in r3. Some of each of these can be seen to be r4-derived (examples are indicated by white arrowheads). D–F are a similar series of sections in the Hoxb1- mutant, in which the situation is similar to that in the wild-type: there is no indication that iC-VO or scattered ipsilateral VO neurons are lost, and some of each are r4-derived. G–L, Ectopic presence of r4-derived neurons in the region containing the iR-VO group. G–L present a series of parasagittal sections through the region containing the iR-VO group in wild-type (G–I) and Hoxb1- (J–L) mice. In this region, Hoxb1- mutants have ectopic r4-derived neurons (examples are indicated by white arrowheads) not seen in wild-type mice. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Scale bar, 200 µm.

Mentions: In contrast to the essentially complete absence of r4-derived vestibulospinal neurons, the r4-derived population of reticulospinal neurons was depleted, but not absent, in both r4 and r5 of Hoxb1- mice (Fig. 3K–V). Similarly, we still found r4-derived scattered ipsi VO neurons in r3 and iC-VO neurons in r4 of the mutant mouse (Fig. 4A–F, examples indicated by arrowheads). Thus, not all r4-derived vestibular projection neurons are lost when Hoxb1 function is eliminated. As expected, the cR-VO and cC-VO groups, which do not derive from r4, were not affected (data not shown).


Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice.

Di Bonito M, Boulland JL, Krezel W, Setti E, Studer M, Glover JC - eNeuro (2015)

Effects of Hoxb1- mutation on vestibulo-ocular neuron groups. A–F, No loss of iC-VO or scattered ipsilateral VO neurons in the Hoxb1- mouse. A–C are a series of parasagittal sections in a wild-type (wt) mouse embryo showing the presence of the few iC-VO neurons in r4 and scattered ipsilateral VO neurons in r3. Some of each of these can be seen to be r4-derived (examples are indicated by white arrowheads). D–F are a similar series of sections in the Hoxb1- mutant, in which the situation is similar to that in the wild-type: there is no indication that iC-VO or scattered ipsilateral VO neurons are lost, and some of each are r4-derived. G–L, Ectopic presence of r4-derived neurons in the region containing the iR-VO group. G–L present a series of parasagittal sections through the region containing the iR-VO group in wild-type (G–I) and Hoxb1- (J–L) mice. In this region, Hoxb1- mutants have ectopic r4-derived neurons (examples are indicated by white arrowheads) not seen in wild-type mice. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Scale bar, 200 µm.
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Related In: Results  -  Collection

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Figure 4: Effects of Hoxb1- mutation on vestibulo-ocular neuron groups. A–F, No loss of iC-VO or scattered ipsilateral VO neurons in the Hoxb1- mouse. A–C are a series of parasagittal sections in a wild-type (wt) mouse embryo showing the presence of the few iC-VO neurons in r4 and scattered ipsilateral VO neurons in r3. Some of each of these can be seen to be r4-derived (examples are indicated by white arrowheads). D–F are a similar series of sections in the Hoxb1- mutant, in which the situation is similar to that in the wild-type: there is no indication that iC-VO or scattered ipsilateral VO neurons are lost, and some of each are r4-derived. G–L, Ectopic presence of r4-derived neurons in the region containing the iR-VO group. G–L present a series of parasagittal sections through the region containing the iR-VO group in wild-type (G–I) and Hoxb1- (J–L) mice. In this region, Hoxb1- mutants have ectopic r4-derived neurons (examples are indicated by white arrowheads) not seen in wild-type mice. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Scale bar, 200 µm.
Mentions: In contrast to the essentially complete absence of r4-derived vestibulospinal neurons, the r4-derived population of reticulospinal neurons was depleted, but not absent, in both r4 and r5 of Hoxb1- mice (Fig. 3K–V). Similarly, we still found r4-derived scattered ipsi VO neurons in r3 and iC-VO neurons in r4 of the mutant mouse (Fig. 4A–F, examples indicated by arrowheads). Thus, not all r4-derived vestibular projection neurons are lost when Hoxb1 function is eliminated. As expected, the cR-VO and cC-VO groups, which do not derive from r4, were not affected (data not shown).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Biology Valrose, UMR 7277, University of Nice Sophia Antipolis, 06108 Nice, France; Institute of Biology Valrose, INSERM, U1091, 06108 Nice, France; Institute of Biology Valrose, CNRS, UMR 7277, 06108 Nice, France.

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- 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- 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.

No MeSH data available.


Related in: MedlinePlus