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. 2021 Feb:19:204-210.
doi: 10.1016/j.cophys.2020.11.001. Epub 2020 Nov 10.

Regulating muscle spindle and Golgi tendon organ proprioceptor phenotypes

Affiliations

Regulating muscle spindle and Golgi tendon organ proprioceptor phenotypes

Niccolò Zampieri et al. Curr Opin Physiol. 2021 Feb.

Abstract

Proprioception is an essential part of motor control. The main sensory subclasses that underlie this feedback control system - muscle spindle and Golgi tendon organ afferents - have been extensively characterized at a morphological and physiological level. More recent studies are beginning to reveal the molecular foundation for distinct proprioceptor subtypes, offering new insights into their developmental ontogeny and phenotypic diversity. This review intends to highlight some of these new findings.

Keywords: Golgi tendon organ; Muscle spindle; Sensory; neuronal identity.

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Conflict of interest statement

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. Proprioceptive muscle afferent subtypes.
A. Schematic indicating the main proprioceptor afferent subtypes as identified based on their association with MS or GTO afferent receptor organs, muscle target, and spinal projection pattern. Mature proprioceptors project to a single muscle in the periphery, and upon entering the spinal cord, bifurcate into a rostral and caudal projecting branch. Collaterals from the main axonal branches project to interneurons or projection neurons at intermediate spinal levels (MS and GTO afferents), and to ventrally located motor neurons (MS afferents). MS afferents form monosynaptic connections with homonymous and synergistically acting motor neurons, but avoid contacts with motor neurons that control antagonistic muscle. Afferent information is also relayed to supraspinal targets, either directly (at forelimb levels), or through projection neurons of the spinocerebellar tracts (hind limb levels). Abbreviations: DRG (dorsal root ganglion), MS (muscle spindle), GTO (Golgi tendon organ), IN (interneuron), MN (motor neuron), SCT (Spinocerebellar tract). B. Distribution of MS and GTO sensory terminals in a p2 neonatal Gluteus muscle. Sensory terminals are genetically marked by a Cre-inducible GFP reporter (Tau:mGFP-iNLZ; activated through a PV:Cre driver). MS group Ia and II afferents cannot yet be distinguished at this point. C. Groups Ia and II MS sensory endings in an adult adductor muscle, genetically marked by tdTomato (tdT) expression, using an intersectional genetic approach based on PV:Cre, Runx3:FlpO, and the Cre- and Flp-recombinase dependent (Ai65) tdT reporter. Scale 20 μm. D. Schematic of the composition of a typical MS. MS consists of several intrafusal muscle fibers (nuclear Bag1, Bag2, and chain). Group Ia afferents innervate the equatorial region of the spindle and associate with nuclear bag 1 and 2 fibers as well as intrafusal nuclear chain fibers. Group II terminals are positioned (bi)lateral to the group Ia terminals (only one group II afferent is shown), and associate with chain fibers and bag 2 fibers (less often), but almost never with bag 1 fibers. In addition to their different intra-spindle termination, group Ia afferents can be distinguished from group II afferents physiologically based on their dynamic sensitivity, their lower activation threshold, and their faster conduction velocity. The polar ends of the intrafusal myofibers are contacted by gamma MNs, which regulate the threshold sensitivity of the sensory terminals for muscle stretch (only one set of motor endings is shown). Depending on their muscle of origin, spindles may consist of different complements of intrafusal fibers. E. Group Ib afferent sensory ending in an adult adductor muscle, marked by tdT using the intersectional genetic approach described in C. Scale 20 μm. F. Sensory terminals of group Ib afferents intertwine between the collagen fibers that attach the extrafusal muscle fibers to tendons or aponeuroses.
Figure 2.
Figure 2.. Mechanisms of development of proprioceptor phenotypes.
A. Early developmental events leading to the acquisition of a generic proprioceptive identity. Shortly after cell cycle exit (e10), Runx3 drives bipotent TrkC+/TrkB+ progenitors to commit to a proprioceptive fate by maintaining expression of TrkC while repressing Shox2, which is required for TrkB expression and cutaneous mechanoreceptor fate–,. At the same time, NT3 expressed in the surroundings of the growing peripheral axons signals through TrkC receptors to promote their survival and outgrowth. B. Control of rostro-caudal organization of proprioceptive muscle subtype identity. Hox gene networks coordinate the organization of stretch reflex circuits at thoracic and limb levels directly through specification of Ia afferent muscle subtype identity - axial and limb muscle respectively - and indirectly by specifying motor neuron identities and expression of factors controlling sensory-motor connectivity,,,. C. Regulation of fine-grained muscle type identity. At a single muscle level proprioceptor identity appears to be regulated by yet to be defined extrinsic factors: in the distal hindlimb, dorsally and ventrally connected Ia afferents are characterized by specific molecular signatures (dorsal: cdh13; sema5a; ventral: crtac1; vstm2b) and induced by the limb mesenchyme. D. MS and GTO afferent identities are marked by selective expression of Heg1 and Pou4f3, as revealed by single cell transcriptional analysis. Failure to detect these molecular markers in prior transcriptomic studies may be attributed to differences in sequencing depth and/or diversity of the neuronal population included in the analysis. Expression of Heg1 and Pou4f3 can be detected from early developmental stages, however maturation and diversification into further subsets continues into postnatal development supporting the existence of multiple molecularly and functionally distinct classes of proprioceptive afferents. Potential sources of the signals that promote proprioceptor diversification may include the mesenchyme, muscle, or the nascent sensory receptor organ.

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