This research will be done in Mexico as an extension of NIH Grant NS37116. Hindbrain reticulospinal neurons are involved in the modulation of spinal visceral and somatic motor responses such as maintenance of posture and the control of cardiovascular and respiratory functions. Two large groups of reticulospinal neurons have been described in the mammalian brainstem, one in the pons and the other in the medulla. These groups are dissimilar in the way they project into the spinal cord (ipsilaterally in the ventral funiculus and bilaterally in the lateral funiculus, respectively) and in their termination sites (pontine fibers terminating more ventrally in the spinal cord than do the medullary ones). The molecular processes underlying the development of these and other morphologically and physiologically distinguishable reticulospinal neuron subtypes, however, remains to be elucidated.
The specific aims of this proposal address two major questions. First, can the different subtypes of reticulospinal neurons be defined on the basis of the transcription factors and neurotransmitters expressed? Second, do these factors functionally predict identity and axonal projection pathway? To answer these questions, fluorescent retrograde labeling will first be used in combination with in situ hybridization and immunostaining to determine the expression of LIM homeodomain and other transcription factors in the subtypes of reticulospinal neurons. A similar strategy will be employed to define their neurotransmitter phenotype. Second, a dominant-negative form of the nuclear LIM interactor will be employed to block LIM homeodomain function and thus to investigate the role these factors play in reticulospinal development. Third, ectopic expression of the transcription factors under study will be attained by in ovo electroporation in chick hindbrain to assess its effect in reticulospinal axon projection. Obtaining the answers to these questions will lead to a better understanding of the molecular determinants of reticulospinal neuron identity and axonal pathfinding. This will, in turn, facilitate the study of the establishment of complex motor circuits. From these efforts, procedures might emerge to restore motor control functions lost by injury or disease.
| Levine, Ariel J; Lewallen, Kathryn A; Pfaff, Samuel L (2012) Spatial organization of cortical and spinal neurons controlling motor behavior. Curr Opin Neurobiol 22:812-21 |
| Cepeda-Nieto, Ana C; Pfaff, Samuel L; Varela-Echavarria, Alfredo (2005) Homeodomain transcription factors in the development of subsets of hindbrain reticulospinal neurons. Mol Cell Neurosci 28:30-41 |
| Myers, Christopher P; Lewcock, Joseph W; Hanson, M Gartz et al. (2005) Cholinergic input is required during embryonic development to mediate proper assembly of spinal locomotor circuits. Neuron 46:37-49 |
