Abstract
BackgroundGamma motor neurons (γ-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. They constitute a distinct subpopulation that differs in morphology, physiology and connectivity from α-MNs, which innervate extrafusal muscle fibers and exert force. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown. Progress on this question has been limited by the absence of molecular markers to specifically distinguish and manipulate γ-MNs. Recently, it was reported that early embryonic γ-MN precursors are dependent on GDNF. Using this knowledge we characterized genetic strategies to label developing γ-MNs based on GDNF receptor expression, showed their strict dependence for survival on muscle spindle-derived GDNF and generated an animal model in which γ-MNs are selectively lost.ResultsIn mice heterozygous for both the Hb9::GFP transgene and a tau-lacZ-labeled (TLZ) allele of the GDNF receptor Gfrα1, we demonstrated that small motor neurons with high Gfrα1-TLZ expression and lacking Hb9::GFP display structural and synaptic features of γ-MNs and are selectively lost in mutants lacking target muscle spindles. Loss of muscle spindles also results in the downregulation of Gfrα1 expression in some large diameter MNs, suggesting that spindle-derived factors may also influence populations of α-MNs with β-skeletofusimotor collaterals. These molecular markers can be used to identify γ-MNs from birth to the adult and to distinguish γ- from β-motor axons in the periphery. We also found that postnatal γ-MNs are also distinguished by low expression of the neuronal nuclear protein (NeuN). With these markers of γ-MN identity, we show after conditional elimination of GDNF from muscle spindles that the survival of γ-MNs is selectively dependent on spindle-derived GDNF during the first 2 weeks of postnatal development.ConclusionNeonatal γ-MNs display a unique molecular profile characterized by the differential expression of a series of markers - Gfrα1, Hb9::GFP and NeuN - and the selective dependence on muscle spindle-derived GDNF. Deletion of GDNF expression from muscle spindles results in the selective elimination of γ-MNs with preservation of the spindle and its sensory innervation. This provides a mouse model with which to explore the specific role of γ-fusimotor activity in motor behaviors.
Highlights
Gamma motor neurons (γ-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch
glial cell line-derived neurotrophic factor (GDNF) receptor (Gfrα1) expression is restricted to subpopulations of motor neurons in the lumbar spinal cord Previous studies have demonstrated that Gfrα1 is expressed in a subset of MNs [25,26,27,28] and that GDNF/ Gfrα1 signaling is required for the survival of spindleinnervating MNs [11,12]
We characterized the subpopulation of Gfrα1+ spinal MNs in mice heterozygous for a null allele of Gfrα1 marked by the expression of tau-lacZ (Gfrα1-TLZ) [15] and the Hb9GFP1Tmj transgene (Hb9::green fluorescent protein (GFP))
Summary
Gamma motor neurons (γ-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown Progress on this question has been limited by the absence of molecular markers to distinguish and manipulate γ-MNs. Recently, it was reported that early embryonic γ-MN precursors are dependent on GDNF. The sensitivity of muscle spindles is actively regulated by a specialized fusimotor system This allows for continuous control of the mechanical sensitivity of spindles over the wide range of lengths and velocities that occur during normal motor behaviors [1]. The advantages of a γ-fusimotor system to control spindle sensitivity independently of force-generating extrafusal muscle fibers are not fully understood, nor are the mechanisms that generate the distinct γ- and α-MN subtypes in mammals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
