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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

Fate mapping of LVST neurons and reticulospinal neurons. A, The b1r4-Cre line, which expresses the Cre recombinase under the control of the Hoxb1 r4 enhancer, is crossed with the ROSA26YY reporter line to label r4 derivatives by YFP expression. B, C, Schematic diagrams of E16.5 brain in the parasagittal plane illustrating the location of YFP-positive r4 and r4 derivatives (green), and the domains of the LVST group and the main population of ipsilaterally projecting reticulospinal (RS) neurons (gray). C, Magenta arrowhead indicates the tracer application site used to retrogradely label vestibulospinal and reticulospinal neurons. D, E, All LVST neurons, including those in r3 and r5, derive from r4. The first panel in each horizontal series is a low-magnification image, with a white square indicating the region shown in the subsequent images. F–H, A population of ipsilaterally projecting RS neurons in r4 and r5 derives from r4. G, Arrowheads indicate LVST axons projecting just dorsal to the RS neurons. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Note that in this and subsequent figures some double-labeled neurons appear to have a magenta nucleus with surrounding yellow to orange cytoplasm; this is because the RDA/BDA can partition into the nucleus where the YFP is weak. Tel, Telencephalon; Di, diencephalon; Mes, mesencephalon; Cb, cerebellum; SC, spinal cord; vnll, ventral nucleus of lateral lemniscus; facial, VIIth cranial (facial) nerve motor nucleus. Scale bars, 200 µm.
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Figure 1: Fate mapping of LVST neurons and reticulospinal neurons. A, The b1r4-Cre line, which expresses the Cre recombinase under the control of the Hoxb1 r4 enhancer, is crossed with the ROSA26YY reporter line to label r4 derivatives by YFP expression. B, C, Schematic diagrams of E16.5 brain in the parasagittal plane illustrating the location of YFP-positive r4 and r4 derivatives (green), and the domains of the LVST group and the main population of ipsilaterally projecting reticulospinal (RS) neurons (gray). C, Magenta arrowhead indicates the tracer application site used to retrogradely label vestibulospinal and reticulospinal neurons. D, E, All LVST neurons, including those in r3 and r5, derive from r4. The first panel in each horizontal series is a low-magnification image, with a white square indicating the region shown in the subsequent images. F–H, A population of ipsilaterally projecting RS neurons in r4 and r5 derives from r4. G, Arrowheads indicate LVST axons projecting just dorsal to the RS neurons. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Note that in this and subsequent figures some double-labeled neurons appear to have a magenta nucleus with surrounding yellow to orange cytoplasm; this is because the RDA/BDA can partition into the nucleus where the YFP is weak. Tel, Telencephalon; Di, diencephalon; Mes, mesencephalon; Cb, cerebellum; SC, spinal cord; vnll, ventral nucleus of lateral lemniscus; facial, VIIth cranial (facial) nerve motor nucleus. Scale bars, 200 µm.

Mentions: Here, we use a transgenic mouse that expresses Cre recombinase under the control of the r4-specific enhancer element of Hoxb1 (b1r4-Cre mouse; Di Bonito et al., 2013a; Fig. 1A) to make a comprehensive characterization of the contribution of r4 to the LVST, cMVST, iMVST, and nearby vestibulo-ocular (VO), vestibular efferent, and reticulospinal neurons. We then test the dependence of these neuron groups on Hoxb1 protein function using a constitutive Hoxb1- mutant mouse, and investigate the resulting behavioral effects. We provide novel evidence about the origins of these projection and efferent neurons, and their dependence on Hoxb1 expression for normal development. Our results also shed light on the role of the LVST and the capacity for functional reorganization when this important component of descending motor control is developmentally compromised.


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)

Fate mapping of LVST neurons and reticulospinal neurons. A, The b1r4-Cre line, which expresses the Cre recombinase under the control of the Hoxb1 r4 enhancer, is crossed with the ROSA26YY reporter line to label r4 derivatives by YFP expression. B, C, Schematic diagrams of E16.5 brain in the parasagittal plane illustrating the location of YFP-positive r4 and r4 derivatives (green), and the domains of the LVST group and the main population of ipsilaterally projecting reticulospinal (RS) neurons (gray). C, Magenta arrowhead indicates the tracer application site used to retrogradely label vestibulospinal and reticulospinal neurons. D, E, All LVST neurons, including those in r3 and r5, derive from r4. The first panel in each horizontal series is a low-magnification image, with a white square indicating the region shown in the subsequent images. F–H, A population of ipsilaterally projecting RS neurons in r4 and r5 derives from r4. G, Arrowheads indicate LVST axons projecting just dorsal to the RS neurons. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Note that in this and subsequent figures some double-labeled neurons appear to have a magenta nucleus with surrounding yellow to orange cytoplasm; this is because the RDA/BDA can partition into the nucleus where the YFP is weak. Tel, Telencephalon; Di, diencephalon; Mes, mesencephalon; Cb, cerebellum; SC, spinal cord; vnll, ventral nucleus of lateral lemniscus; facial, VIIth cranial (facial) nerve motor nucleus. Scale bars, 200 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4697082&req=5

Figure 1: Fate mapping of LVST neurons and reticulospinal neurons. A, The b1r4-Cre line, which expresses the Cre recombinase under the control of the Hoxb1 r4 enhancer, is crossed with the ROSA26YY reporter line to label r4 derivatives by YFP expression. B, C, Schematic diagrams of E16.5 brain in the parasagittal plane illustrating the location of YFP-positive r4 and r4 derivatives (green), and the domains of the LVST group and the main population of ipsilaterally projecting reticulospinal (RS) neurons (gray). C, Magenta arrowhead indicates the tracer application site used to retrogradely label vestibulospinal and reticulospinal neurons. D, E, All LVST neurons, including those in r3 and r5, derive from r4. The first panel in each horizontal series is a low-magnification image, with a white square indicating the region shown in the subsequent images. F–H, A population of ipsilaterally projecting RS neurons in r4 and r5 derives from r4. G, Arrowheads indicate LVST axons projecting just dorsal to the RS neurons. RDA/BDA labeling is depicted by magenta, YFP immunolabeling is depicted by green, and double labeling appears as varying hues of yellow and orange. Note that in this and subsequent figures some double-labeled neurons appear to have a magenta nucleus with surrounding yellow to orange cytoplasm; this is because the RDA/BDA can partition into the nucleus where the YFP is weak. Tel, Telencephalon; Di, diencephalon; Mes, mesencephalon; Cb, cerebellum; SC, spinal cord; vnll, ventral nucleus of lateral lemniscus; facial, VIIth cranial (facial) nerve motor nucleus. Scale bars, 200 µm.
Mentions: Here, we use a transgenic mouse that expresses Cre recombinase under the control of the r4-specific enhancer element of Hoxb1 (b1r4-Cre mouse; Di Bonito et al., 2013a; Fig. 1A) to make a comprehensive characterization of the contribution of r4 to the LVST, cMVST, iMVST, and nearby vestibulo-ocular (VO), vestibular efferent, and reticulospinal neurons. We then test the dependence of these neuron groups on Hoxb1 protein function using a constitutive Hoxb1- mutant mouse, and investigate the resulting behavioral effects. We provide novel evidence about the origins of these projection and efferent neurons, and their dependence on Hoxb1 expression for normal development. Our results also shed light on the role of the LVST and the capacity for functional reorganization when this important component of descending motor control is developmentally compromised.

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