Material below summarizes the article Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice, published on November 23, 2015, in eNeuro and authored by Maria Di Bonito, Jean-Luc Boulland, Wojciech Krezel, Eya Setti, Michèle Studer, and Joel C. Glover.
Sense of balance is an essential element in our relationship to the external world. Lose it and we risk becoming disoriented, which could prove fatal if it occurs at an inopportune moment. Incorporating a sensorimotor system that detects changes in position and generates compensatory movements was therefore an early evolutionary innovation — one that nearly all multicellular animals possess and has developed into the vestibular system in humans and other vertebrates.
Given its ancient origins, one might expect that constructing the vestibular system during embryonic and fetal development relies on highly conserved genetic programs. Several indications of this have been reported previously, including work from our laboratories. But there is still little knowledge about how this is achieved.
In this study, we took advantage of mouse transgenics to assess the role of a specific developmental patterning gene, Hoxb1, in creating some of the principal neuron groups involved in vestibular function. We focused on the neuron group that gives rise to the lateral vestibulospinal tract (LVST), the pathway that initiates limb and trunk movements when we trip or fall. We used a Hoxb1 enhancer element to express a fluorescent reporter protein in the domain of the brainstem from which the LVST group originates, and we used a constitutive Hoxb1 null mutation to prevent the expression of Hoxb1 in that domain.
Using the reporter protein expression, we found that the LVST group derives in its entirety from the domain of the brainstem, rhombomere 4 (r4), which is specifically characterized by Hoxb1 expression. This corroborated earlier reports. We also found that other vestibular neuron groups derived entirely or in part from r4, as did a few reticulospinal neurons that also mediate communication between the brainstem and the spinal cord.
Using the constitutive Hoxb1 null mutation, we found that mice without Hoxb1 expression lack the LVST. They also lack the other vestibular neuron groups or portions of groups that derive from r4. The r4-derived reticulospinal neurons, by contrast, were less numerous but still present. Thus, Hoxb1 is critically involved in the development of certain types of vestibular neurons and is absolutely essential for the development of the LVST group and its axonal projections to the spinal cord.
One might expect that without an LVST, body movements generated by the vestibular system would be impaired. We therefore assessed the behavioral effects of lacking the LVST.
As expected, mice at birth lacking the LVST exhibited greatly diminished vestibulospinal limb reflexes. This deficit did not persist, however. During the ensuing week, vestibulospinal reflexes recovered to near normal levels. At present, we do not know how this improvement occurs. A likely hypothesis is that a parallel pathway, for example mediated by vestibular inputs to reticulospinal neurons normally present but with only an auxiliary function, gradually takes over for the missing LVST.
Aside from the clear but transient effect on vestibulospinal reflexes, mice lacking the LVST appeared relatively normal with respect to general motor behavior. They could walk, swim, and explore an open field, although they seemed a little unsteady when rearing on their hind feet.
We did observe, however, some subtle defects when we investigated locomotor skills in more detail. We noted that the mutant mice tended to slip more often when navigating a notched beam that required stepping over regularly spaced gaps, and during this test and when swimming they tended to use synchronous movements of the limbs more often than control mice, which relied almost exclusively on alternating limb movements.
Thus, the behavioral effects of knocking out the Hoxb1 gene included some deficits expected from the loss of the LVST, which nonetheless resolved over time, and some unexpected deficits. It is unclear whether the unexpected hindlimb synchrony is due to the loss of the LVST, since it could be explained for example by the numerical deficit in r4-derived reticulospinal neurons. However, it raises the intriguing possibility that the LVST not only functions to mediate vestibulospinal reflexes, but also may contribute in more subtle ways to regulating the motor output of the spinal cord.
Loss of Projections, Functional Compensation, and Residual Deficits in the Mammalian Vestibulospinal System of Hoxb1-Deficient Mice. Maria Di Bonito, Jean-Luc Boulland, Wojciech Krezel, Eya Setti, Michèle Studer, Joel C. Glover. eNeuro Nov 2015, DOI: 10.1523/ENEURO.0096-15.2015