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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

Loss of vestibulospinal neurons and depletion of reticulospinal neurons in the Hoxb1- mutant. A–J, Loss of vestibulospinal neurons. Comparison of the two vestibulospinal groups that derive wholly or partly from r4 in the wild-type (LVST, A–C; cMVST, D, E) and the Hoxb1- mutant (F–J) shows a complete absence of r4-derived LVST and cMVST neurons. The white arrowheads in D indicate examples of r4-derived cMVST neurons. Those in F–H indicate examples of non-r4-derived spinally projecting neurons in the Hoxb1- mutant in the area where the LVST is normally located. The green arrowheads in I and J indicate non-spinally projecting r4-derived cells that migrate into r3 within the vestibular nuclear complex in the Hoxb1- mutant. K–P, Depletion of r4-derived reticulospinal neurons. Reticulospinal neurons derived from r4 (white arrowheads) are more numerous in the wild-type (K–M) than in the Hoxb1- mutant (N–P). RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Q–V, Examples of confocal z-stacks to demonstrate double labeling, in this case of two reticulospinal neurons. Each panel shows a z-stack viewed in the x–y plane and from the x–z and y–z faces, with x and y transects intersecting at a reticulospinal neuron that is double labeled (one in Q–S, another in T–V). In each row of panels, the right panel shows only RDA (magenta), the middle panel shows only YFP (green), and the left panel shows a merge of the two (note that here the magenta and green combine to create a pale white, as opposed to the yellow/orange that depicts double labeling in the panels above; see Materials and Methods). RS, Reticulospinal neurons. Scale bars: A–P, 200 µm; Q–V, 20 µm.
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Figure 3: Loss of vestibulospinal neurons and depletion of reticulospinal neurons in the Hoxb1- mutant. A–J, Loss of vestibulospinal neurons. Comparison of the two vestibulospinal groups that derive wholly or partly from r4 in the wild-type (LVST, A–C; cMVST, D, E) and the Hoxb1- mutant (F–J) shows a complete absence of r4-derived LVST and cMVST neurons. The white arrowheads in D indicate examples of r4-derived cMVST neurons. Those in F–H indicate examples of non-r4-derived spinally projecting neurons in the Hoxb1- mutant in the area where the LVST is normally located. The green arrowheads in I and J indicate non-spinally projecting r4-derived cells that migrate into r3 within the vestibular nuclear complex in the Hoxb1- mutant. K–P, Depletion of r4-derived reticulospinal neurons. Reticulospinal neurons derived from r4 (white arrowheads) are more numerous in the wild-type (K–M) than in the Hoxb1- mutant (N–P). RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Q–V, Examples of confocal z-stacks to demonstrate double labeling, in this case of two reticulospinal neurons. Each panel shows a z-stack viewed in the x–y plane and from the x–z and y–z faces, with x and y transects intersecting at a reticulospinal neuron that is double labeled (one in Q–S, another in T–V). In each row of panels, the right panel shows only RDA (magenta), the middle panel shows only YFP (green), and the left panel shows a merge of the two (note that here the magenta and green combine to create a pale white, as opposed to the yellow/orange that depicts double labeling in the panels above; see Materials and Methods). RS, Reticulospinal neurons. Scale bars: A–P, 200 µm; Q–V, 20 µm.

Mentions: Next, we used retrograde labeling in the Hoxb1- mouse (labeling vestibulospinal and reticulospinal neurons unilaterally, n = 3; labeling vestibulo-ocular neurons unilaterally, n = 3) to test the dependence of r4-derived neuron populations on Hoxb1 expression. First, we demonstrated that the LVST neuron group was severely depleted if not absent in E16.5 Hoxb1- embryos (Fig. 3F–H). This is in accordance with the finding by Chen et al. (2012) that vestibulospinal neurons in the lateral vestibulospinal nucleus are lost in a different Hoxb1- mouse strain. No retrogradely labelled YFP+ neurons were found in r3, r4, or r5 in the region that normally contains the LVST group (Fig. 3A–C,F–H), and there was no sign of YFP+ axons along the trajectory of the LVST. A few retrogradely labeled YFP-negative neurons were present in the area normally occupied by the LVST (Fig. 3F–H, arrowheads). These, however, numbered only a few tens of neurons (Fig. 3F–H, example where they are particularly numerous), whereas the LVST group normally contains many hundreds and perhaps well over a thousand neurons. The identity of these non-r4-derived neurons remains unclear.


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)

Loss of vestibulospinal neurons and depletion of reticulospinal neurons in the Hoxb1- mutant. A–J, Loss of vestibulospinal neurons. Comparison of the two vestibulospinal groups that derive wholly or partly from r4 in the wild-type (LVST, A–C; cMVST, D, E) and the Hoxb1- mutant (F–J) shows a complete absence of r4-derived LVST and cMVST neurons. The white arrowheads in D indicate examples of r4-derived cMVST neurons. Those in F–H indicate examples of non-r4-derived spinally projecting neurons in the Hoxb1- mutant in the area where the LVST is normally located. The green arrowheads in I and J indicate non-spinally projecting r4-derived cells that migrate into r3 within the vestibular nuclear complex in the Hoxb1- mutant. K–P, Depletion of r4-derived reticulospinal neurons. Reticulospinal neurons derived from r4 (white arrowheads) are more numerous in the wild-type (K–M) than in the Hoxb1- mutant (N–P). RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Q–V, Examples of confocal z-stacks to demonstrate double labeling, in this case of two reticulospinal neurons. Each panel shows a z-stack viewed in the x–y plane and from the x–z and y–z faces, with x and y transects intersecting at a reticulospinal neuron that is double labeled (one in Q–S, another in T–V). In each row of panels, the right panel shows only RDA (magenta), the middle panel shows only YFP (green), and the left panel shows a merge of the two (note that here the magenta and green combine to create a pale white, as opposed to the yellow/orange that depicts double labeling in the panels above; see Materials and Methods). RS, Reticulospinal neurons. Scale bars: A–P, 200 µm; Q–V, 20 µm.
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Figure 3: Loss of vestibulospinal neurons and depletion of reticulospinal neurons in the Hoxb1- mutant. A–J, Loss of vestibulospinal neurons. Comparison of the two vestibulospinal groups that derive wholly or partly from r4 in the wild-type (LVST, A–C; cMVST, D, E) and the Hoxb1- mutant (F–J) shows a complete absence of r4-derived LVST and cMVST neurons. The white arrowheads in D indicate examples of r4-derived cMVST neurons. Those in F–H indicate examples of non-r4-derived spinally projecting neurons in the Hoxb1- mutant in the area where the LVST is normally located. The green arrowheads in I and J indicate non-spinally projecting r4-derived cells that migrate into r3 within the vestibular nuclear complex in the Hoxb1- mutant. K–P, Depletion of r4-derived reticulospinal neurons. Reticulospinal neurons derived from r4 (white arrowheads) are more numerous in the wild-type (K–M) than in the Hoxb1- mutant (N–P). RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Q–V, Examples of confocal z-stacks to demonstrate double labeling, in this case of two reticulospinal neurons. Each panel shows a z-stack viewed in the x–y plane and from the x–z and y–z faces, with x and y transects intersecting at a reticulospinal neuron that is double labeled (one in Q–S, another in T–V). In each row of panels, the right panel shows only RDA (magenta), the middle panel shows only YFP (green), and the left panel shows a merge of the two (note that here the magenta and green combine to create a pale white, as opposed to the yellow/orange that depicts double labeling in the panels above; see Materials and Methods). RS, Reticulospinal neurons. Scale bars: A–P, 200 µm; Q–V, 20 µm.
Mentions: Next, we used retrograde labeling in the Hoxb1- mouse (labeling vestibulospinal and reticulospinal neurons unilaterally, n = 3; labeling vestibulo-ocular neurons unilaterally, n = 3) to test the dependence of r4-derived neuron populations on Hoxb1 expression. First, we demonstrated that the LVST neuron group was severely depleted if not absent in E16.5 Hoxb1- embryos (Fig. 3F–H). This is in accordance with the finding by Chen et al. (2012) that vestibulospinal neurons in the lateral vestibulospinal nucleus are lost in a different Hoxb1- mouse strain. No retrogradely labelled YFP+ neurons were found in r3, r4, or r5 in the region that normally contains the LVST group (Fig. 3A–C,F–H), and there was no sign of YFP+ axons along the trajectory of the LVST. A few retrogradely labeled YFP-negative neurons were present in the area normally occupied by the LVST (Fig. 3F–H, arrowheads). These, however, numbered only a few tens of neurons (Fig. 3F–H, example where they are particularly numerous), whereas the LVST group normally contains many hundreds and perhaps well over a thousand neurons. The identity of these non-r4-derived neurons remains unclear.

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