ABSTRACT
Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia-motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional.
Subject(s)
Motor Neurons/physiology , Muscle Spindles/physiology , Reflex, Monosynaptic/physiology , Actins/genetics , Animals , Animals, Newborn , Dose-Response Relationship, Drug , Early Growth Response Protein 3/genetics , Electric Stimulation , Humans , In Vitro Techniques , Mice , Mice, Transgenic , Motor Neurons/drug effects , Muscle Spindles/drug effects , Muscle, Skeletal/physiology , Nerve Growth Factors/pharmacology , Neurons, Afferent/physiology , Reaction Time/drug effects , Reaction Time/genetics , Receptor, ErbB-2/deficiency , Reflex, Monosynaptic/drug effects , Reflex, Monosynaptic/genetics , Spinal Cord/cytology , Synaptic Potentials/drug effects , Synaptic Potentials/genetics , Synaptic Potentials/physiologyABSTRACT
Significant advances have been made during the past few years in our understanding of how the spinal monosynaptic reflex develops. Transcription factors in the Neurogenin, Runt, ETS, and LIM families control sequential steps of the specification of various subtypes of dorsal root ganglia sensory neurons. The initiation of muscle spindle differentiation requires neuregulin 1, derived from Ia afferent sensory neurons, and signaling through ErbB receptors in intrafusal muscle fibers. Several retrograde signals from the periphery are important for the establishment of late connectivity in the reflex circuit. Finally, neurotrophin 3 released from muscle spindles regulates the strength of sensory-motor connections within the spinal cord postnatally.