Genetic Identification of Spinal Interneurons that Coordinate Left-Right Locomotor Activity Necessary for Walking Movements

Abstract

The sequential stepping of left and right limbs is a fundamental motor behavior that underlies walking movements. This relatively simple locomotor behavior is generated by the rhythmic activity of motor neurons under the control of spinal neural networks known as central pattern generators (CPGs) that comprise multiple interneuron cell types. Little, however, is known about the identity and contribution of defined interneuronal populations to mammalian locomotor behaviors. We show a discrete subset of commissural spinal interneurons, whose fate is controlled by the activity of the homeobox gene Dbx1, has a critical role in controlling the left-right alternation of motor neurons innervating hindlimb muscles. Dbx1 mutant mice lacking these ventral interneurons exhibit an increased incidence of cobursting between left and right flexor/extensor motor neurons during drug-induced locomotion. Together, these findings identify Dbx1-dependent interneurons as key components of the spinal locomotor circuits that control stepping movements in mammals.

Strategies for delineating spinal locomotor rhythm-generating networks and the possible role of Hb9 interneurones in rhythmogenesis

“…Each of these classes of interneurone (V0, V1, V2 and V3) can be defined based upon the selective expression of transcription factors in that population. The use of molecular biological approaches to alter the expression or activity of these specific classes of interneurones has allowed for the identification and study of populations of neurones derived from these domains (Gosgnach et al, 2006;Lanuza et al, 2004). Furthermore, by using fluorescent proteins which are driven by the promoters for these transcription factors, it is possible to study and define these populations anatomically (Alvarez et al, 2005) or physiologically (Hinckley et al, 2005;Wilson et al, 2005) in the post-natal animal.…”

“…Nevertheless, there have been significant challenges to progress beyond Getting's second step. In recent years, progress has been made in the identification of neurones involved in some aspects of locomotion (step 3), such as right-left coordination (Butt and Kiehn, 2003;Lanuza et al, 2004;Nakayama et al, 2002;Zhong et al, 2006). However, neither the precise connectivity of locomotor-related spinal interneurones nor their intrinsic properties have been defined.…”

Target selection of proprioceptive and motor axon synapses on neonatal V1‐derived Ia inhibitory interneurons and Renshaw cells

“…Diversification of other ventral horn interneuronal populations has also been noted during embryonic development. V0 interneurons are divided in embryo into dorsal and ventral groups characterized by differential expression of the transcription factor Evx1 and neurotransmitter content (V0d are inhibitory while V0v are glutamatergic; Lanuza et al, 2004;Goulding, 2009). More recently, two more interneuronal groups were found to originate from the p0 domain, one cholinergic (V0c) and one glutamatergic (V0g), both characterized by the expression of the transcription factor Pitx2.…”

EphA4 defines a class of excitatory locomotor-related interneurons

“…These techniques allow incorporation of molecular markers such as ␤-galactosidase (␤-gal) or green fluorescent protein (GFP) under the control of selective promoters to provide important means of identifying and targeting specific neuronal populations (3)(4)(5)(6)(7). Moreover, knockouts of fate-determining transcription factors (8) or transmitter systems active during development (9) provide a powerful tool to investigate the overall structure of a network and how it is assembled during development. Such studies are particularly relevant in mammalian systems where it has been an immense task to characterize the principle constituents of neural networks from both developmental genetics (1) and physiological (10)(11)(12) perspectives.…”