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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

Behavioral effects of the Hoxb1- mutation in adult mice: linear swimming test and notched beam test. A–C, Linear swimming test. A, B, Examples of alternating hindlimb swimming movements in wild-type mice (A) and synchronous hindlimb swimming movements in Hoxb1- mice (B). Green and red traces delineate respectively the hindlimb closest to and farthest from the camera. C, Comparison of average number of synchronous hindlimb strokes. D, Comparison of the average time required to swim the total distance of 1 m. E–I, Notched beam test. E, Comparison of average time required to traverse the beam. F, G, Examples of alternating and synchronous locomotor movements in wild-type and Hoxb1- mice, respectively. H, Comparison of the number of slips made while traversing the beam. I, Comparison of the number of hops made while traversing the beam. Error bars represent SEM. Significant differences with respect to control mice were identified using the PLSD Fisher test: *p < 0.05; **p < 0.01.
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Figure 8: Behavioral effects of the Hoxb1- mutation in adult mice: linear swimming test and notched beam test. A–C, Linear swimming test. A, B, Examples of alternating hindlimb swimming movements in wild-type mice (A) and synchronous hindlimb swimming movements in Hoxb1- mice (B). Green and red traces delineate respectively the hindlimb closest to and farthest from the camera. C, Comparison of average number of synchronous hindlimb strokes. D, Comparison of the average time required to swim the total distance of 1 m. E–I, Notched beam test. E, Comparison of average time required to traverse the beam. F, G, Examples of alternating and synchronous locomotor movements in wild-type and Hoxb1- mice, respectively. H, Comparison of the number of slips made while traversing the beam. I, Comparison of the number of hops made while traversing the beam. Error bars represent SEM. Significant differences with respect to control mice were identified using the PLSD Fisher test: *p < 0.05; **p < 0.01.

Mentions: To assess motor capability with less dependence on weight-bearing equilibrium, we performed the linear 1 m swimming test, which elicits non-weight-bearing locomotion in which hindlimbs drive forward propulsion while forelimbs are held in a static flexed position (Fig. 8A–E). Hoxb1- mice displayed the same body position and head orientation during swimming as control mice (Fig. 8A,B), but instead of continuously using alternating hindlimb movements, they occasionally extended their hindlimbs synchronously (Fig. 8B; Videos 1, 2). Interposition of synchronous hindlimb movements was significantly more frequent in Hoxb1- mice than in control mice (RMANOVA, F(1,15) = 10.5, p < 0.005 for main effect of the Hoxb1- mutation; Fig. 8C). Because these synchronous hindlimb movements interrupted the smooth forward motion of swimming, their generation is likely related to the tendency for Hoxb1- mice to take longer to swim the 1 m distance, a time that became statistically significant on the last trial (Hoxb1- mice, 3.8 ± 0.3 s vs control mice 5.4 ± 0.9 s; p = 0.03; Fig. 8D).


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)

Behavioral effects of the Hoxb1- mutation in adult mice: linear swimming test and notched beam test. A–C, Linear swimming test. A, B, Examples of alternating hindlimb swimming movements in wild-type mice (A) and synchronous hindlimb swimming movements in Hoxb1- mice (B). Green and red traces delineate respectively the hindlimb closest to and farthest from the camera. C, Comparison of average number of synchronous hindlimb strokes. D, Comparison of the average time required to swim the total distance of 1 m. E–I, Notched beam test. E, Comparison of average time required to traverse the beam. F, G, Examples of alternating and synchronous locomotor movements in wild-type and Hoxb1- mice, respectively. H, Comparison of the number of slips made while traversing the beam. I, Comparison of the number of hops made while traversing the beam. Error bars represent SEM. Significant differences with respect to control mice were identified using the PLSD Fisher test: *p < 0.05; **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Behavioral effects of the Hoxb1- mutation in adult mice: linear swimming test and notched beam test. A–C, Linear swimming test. A, B, Examples of alternating hindlimb swimming movements in wild-type mice (A) and synchronous hindlimb swimming movements in Hoxb1- mice (B). Green and red traces delineate respectively the hindlimb closest to and farthest from the camera. C, Comparison of average number of synchronous hindlimb strokes. D, Comparison of the average time required to swim the total distance of 1 m. E–I, Notched beam test. E, Comparison of average time required to traverse the beam. F, G, Examples of alternating and synchronous locomotor movements in wild-type and Hoxb1- mice, respectively. H, Comparison of the number of slips made while traversing the beam. I, Comparison of the number of hops made while traversing the beam. Error bars represent SEM. Significant differences with respect to control mice were identified using the PLSD Fisher test: *p < 0.05; **p < 0.01.
Mentions: To assess motor capability with less dependence on weight-bearing equilibrium, we performed the linear 1 m swimming test, which elicits non-weight-bearing locomotion in which hindlimbs drive forward propulsion while forelimbs are held in a static flexed position (Fig. 8A–E). Hoxb1- mice displayed the same body position and head orientation during swimming as control mice (Fig. 8A,B), but instead of continuously using alternating hindlimb movements, they occasionally extended their hindlimbs synchronously (Fig. 8B; Videos 1, 2). Interposition of synchronous hindlimb movements was significantly more frequent in Hoxb1- mice than in control mice (RMANOVA, F(1,15) = 10.5, p < 0.005 for main effect of the Hoxb1- mutation; Fig. 8C). Because these synchronous hindlimb movements interrupted the smooth forward motion of swimming, their generation is likely related to the tendency for Hoxb1- mice to take longer to swim the 1 m distance, a time that became statistically significant on the last trial (Hoxb1- mice, 3.8 ± 0.3 s vs control mice 5.4 ± 0.9 s; p = 0.03; Fig. 8D).

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