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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 vestibular efferent neurons in the Hoxb1- mutant. A–B', In situ hybridization for Gata3 transcripts (A, A') and Hoxb1-driven expression of YFP (B, B') in wild-type (wt) and Hoxb1- mouse embryos. Gata3 in situ hybridization in wild-type mice labels the vestibular efferent neurons (VEN) in the specific region of r4 where they differentiate (A, B, arrows). In Hoxb1- mice, this region is devoid of Gata3 expression (A', *). The application of DiI to the peripheral nerves in the inner ear at P8 retrogradely labels vestibular efferent neurons in wild-type mice (C, VEN), but not in Hoxb1- mice (C', *).
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Figure 5: Loss of vestibular efferent neurons in the Hoxb1- mutant. A–B', In situ hybridization for Gata3 transcripts (A, A') and Hoxb1-driven expression of YFP (B, B') in wild-type (wt) and Hoxb1- mouse embryos. Gata3 in situ hybridization in wild-type mice labels the vestibular efferent neurons (VEN) in the specific region of r4 where they differentiate (A, B, arrows). In Hoxb1- mice, this region is devoid of Gata3 expression (A', *). The application of DiI to the peripheral nerves in the inner ear at P8 retrogradely labels vestibular efferent neurons in wild-type mice (C, VEN), but not in Hoxb1- mice (C', *).

Mentions: Another population of vestibular neurons is the group of cholinergic vestibular efferent neurons that innervates hair cells and calyx afferent endings in the vestibular end organs in the inner ear (Highstein 1991). Vestibular efferent neurons, similar to cochlear efferent neurons, originate from ventral r4 and express high levels of Gata2 and Gata3 (Tiveron et al., 2003). No Gata3 expression was detected in the vestibular efferent neuron domain in E14.5 Hoxb1- mice (n = 3; Fig. 5A,A'), commensurate with an absence of inner ear efferent neurons (Di Bonito et al., 2013a). To confirm the absence of vestibular efferents at postnatal stages when connectivity is established, DiI crystals were inserted into the inner ears of wild-type mice (n = 3) and Hoxb1- mice (n = 3) at P8. No efferent neurons were retrogradely labeled at this stage in the mutant mice (Fig. 5C,C'), confirming their absence and excluding the presence of any other ectopic source of efferent input to the inner ear. Thus, vestibular projection neurons and vestibular efferent neurons derived from r4 are critically dependent on the expression and function of Hoxb1 protein.


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 vestibular efferent neurons in the Hoxb1- mutant. A–B', In situ hybridization for Gata3 transcripts (A, A') and Hoxb1-driven expression of YFP (B, B') in wild-type (wt) and Hoxb1- mouse embryos. Gata3 in situ hybridization in wild-type mice labels the vestibular efferent neurons (VEN) in the specific region of r4 where they differentiate (A, B, arrows). In Hoxb1- mice, this region is devoid of Gata3 expression (A', *). The application of DiI to the peripheral nerves in the inner ear at P8 retrogradely labels vestibular efferent neurons in wild-type mice (C, VEN), but not in Hoxb1- mice (C', *).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Loss of vestibular efferent neurons in the Hoxb1- mutant. A–B', In situ hybridization for Gata3 transcripts (A, A') and Hoxb1-driven expression of YFP (B, B') in wild-type (wt) and Hoxb1- mouse embryos. Gata3 in situ hybridization in wild-type mice labels the vestibular efferent neurons (VEN) in the specific region of r4 where they differentiate (A, B, arrows). In Hoxb1- mice, this region is devoid of Gata3 expression (A', *). The application of DiI to the peripheral nerves in the inner ear at P8 retrogradely labels vestibular efferent neurons in wild-type mice (C, VEN), but not in Hoxb1- mice (C', *).
Mentions: Another population of vestibular neurons is the group of cholinergic vestibular efferent neurons that innervates hair cells and calyx afferent endings in the vestibular end organs in the inner ear (Highstein 1991). Vestibular efferent neurons, similar to cochlear efferent neurons, originate from ventral r4 and express high levels of Gata2 and Gata3 (Tiveron et al., 2003). No Gata3 expression was detected in the vestibular efferent neuron domain in E14.5 Hoxb1- mice (n = 3; Fig. 5A,A'), commensurate with an absence of inner ear efferent neurons (Di Bonito et al., 2013a). To confirm the absence of vestibular efferents at postnatal stages when connectivity is established, DiI crystals were inserted into the inner ears of wild-type mice (n = 3) and Hoxb1- mice (n = 3) at P8. No efferent neurons were retrogradely labeled at this stage in the mutant mice (Fig. 5C,C'), confirming their absence and excluding the presence of any other ectopic source of efferent input to the inner ear. Thus, vestibular projection neurons and vestibular efferent neurons derived from r4 are critically dependent on the expression and function of Hoxb1 protein.

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