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Published in final edited form as: Dev Dyn. 2018 Jan 17;247(4):581–587. doi: 10.1002/dvdy.24611

Molecular mechanisms underlying monosynaptic sensory-motor circuit development in the spinal cord

Fumiyasu Imai 1, Yutaka Yoshida 1,*
PMCID: PMC5854510  NIHMSID: NIHMS926623  PMID: 29226492

Abstract

Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key components of the sensory system, are located in the dorsal root ganglia and project axons both centrally to the spinal cord and peripherally to muscles and tendons, communicating peripheral information about the body to the CNS. Changes in muscle length detected by muscle spindles, and tension variations in tendons conveyed by golgi tendon organs, are communicated to the CNS through group Ia/II, and Ib proprioceptive sensory afferents, respectively. Group Ib proprioceptive sensory neurons connect with motor neurons indirectly via spinal interneurons, whereas group Ia/II axons form both direct (monosynaptic) and indirect connections with motor neurons. Although monosynaptic sensory-motor circuits between spindle proprioceptive sensory neurons and motor neurons have been extensively studied since 1950s, the molecular mechanisms underlying their formation and upkeep have only recently begun to be understood. We will discuss our current understanding of the molecular foundation of monosynaptic circuit development and maintenance involving proprioceptive sensory neurons and motor neurons in the mammalian spinal cord.

Introduction

The activity of motor neurons, which deliver the final instructions to muscles for all motor behaviors, is coordinated, in part, by proprioceptive sensory neurons, which convey peripheral information about muscle contractions to motor neurons as a feedback system to generate appropriate motor responses. Proprioceptive sensory neurons, whose cell bodies are located in the dorsal root ganglia (DRGs), are subdivided into large diameter neurons (groups Ia and Ib) and medium diameter neurons (group II) (Lloyd, 1943; Brown, 1981) (Figure 1). Both group Ia and II proprioceptive sensory neurons detect changes in muscle length and project axons peripherally to muscle spindles, and centrally to the intermediate and ventral spinal cord where they form both direct or indirect connections with motor neurons. In contrast, group Ib proprioceptive sensory neurons, which detect changes in muscle tension, send axons peripherally to golgi tendon organs, and centrally to the intermediate spinal cord where they form only indirect connections with motor neurons via interneurons. We will focus on proprioceptive sensory neurons in DRGs in this review, however, it is worthy to note that cell bodies of a small subset of proprioceptive sensory neurons are also located in the brainstem conveying information to the CNS about jaw and facial muscle movements (Zhang et al., 2012; Stanek et al., 2014).

Figure 1.

Figure 1

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Schematic drawing of Ia/II and Ib proprioceptive sensory neurons

Ia/II proprioceptive sensory neurons (Ia//II) are located in the dorsal root ganglia (DRGs) and project to specific alpha motor neurons (MNs) which project axons back to the same muscle. Ib Proprioceptive sensory neurons (Ib) innervate golgi tendon organs (GTOs). Group Ia and II proprioceptive sensory neurons form monosynaptic connections with motor neurons, whereas all (Ia, Ib and II) proprioceptive connect with spinal cord interneurons (INs), and then MNs.

In mice, proprioceptive sensory afferents reach the spinal cord and muscles around embryonic day 10.5 (E10.5) (Ozaki and Snider, 1997; Huettl et al., 2011). Then, axons penetrate spinal cord at dorsal root entry zone around E12.5 and form monosynaptic connections with motor neurons by E17 (Mears and Frank, 1997; Ozaki and Snider, 1997). Group Ia/II proprioceptive sensory afferents form monosynaptic connections with specific motor neuron targets that innervate either the same muscle or related muscles that are synergistic, but not antagonistic muscles. Mice lacking proprioceptive sensory neurons or muscle spindles show defects in appropriate muscle activation in vivo (Akay et al., 2014; Takeoka et al., 2014). The simplicity of monosynaptic sensory-motor circuits make them an effective model system to study the molecular mechanisms underlying the different steps of neural circuit formation such as axonal elongation, synaptic specificity, synapse formation, and circuit maintenance. In contrast, much less is known about the formation of the more complex connections between proprioceptive sensory neurons and interneurons in the spinal cord, and we will thus be centering this review on the development of monosynaptic sensory-motor circuits, particularly the establishment of proprioceptive sensory neuron connections with peripheral tissues and the spinal cord, and mechanisms that preserve and maintain these circuits beyond the late embryonic stages.

(1) Interactions between proprioceptive sensory axons and target muscles

Monosynaptic sensory-motor circuit development begins with the proper innervation of limb muscles by proprioceptive sensory afferents. Recent studies have shown that signaling by target limb mesenchyme plays an important role in establishing proprioceptor identity, while molecular communication from proprioceptive sensory afferents directly impacts muscle spindle development.

Poliak and colleagues found that proprioceptive sensory neurons projecting to dorsal limbs and ventral limbs had different molecular identities which were alterable by changing the dorsoventral character of the target limb mesenchyme (Poliak et al., 2016). Dorsal limb-projecting proprioceptors expressed cadherin 13 (Cdh13) and semaphorin 5a (Sema5a), while cartilage acidic protein 1 (Crtac1) was uniquely expressed by ventral limb-projecting proprioceptive sensory neurons. When the limb mesenchyme’s dorsal and ventral character was changed, the expression profiles of Cdh13, Sema5a, and Crtac1 also changed, suggesting that signals from the limb mesenchyme help establish the molecular identities of proprioceptive sensory neurons (Poliak et al., 2016).

Studies in mice revealed that proper muscle spindle development is essential for establishment of monosynaptic sensory-motor circuits. Group Ia/II proprioceptive axons innervate the intrafusal muscle fibers of muscle spindles, and transduce changes in intrafusal fiber length into electrical signals (Maier, 1997; Proske and Gandevia, 2012; Bewick and Banks, 2015). Muscle spindle sensitivity is regulated by these gamma motor neurons which do not receive direct connections from proprioceptive sensory neurons (Hunt and Kuffler, 1951; Eccles et al., 1957; Zampieri et al., 2014).

The transcription factor early growth response protein 3 (Egr3) is expressed in both intrafusal fibers and proprioceptive sensory neurons, and regulates muscle spindle development, which impacts their innervation by proprioceptive axons. Egr3 mutant mice show reduced spindle fiber numbers and exhibit gait ataxia (Tourtellotte and Milbrandt, 1998; Akay et al., 2014; Takeoka et al., 2014; Oliveira Fernandes and Tourtellotte, 2015). Targeted deletion of Egr3 in sensory neurons does not cause muscle spindle defects, therefore Egr3 from the intrafusal fibers seems to be the key contributor to proper muscle spindle development (Oliveira Fernandes and Tourtellotte, 2015).

Innervation by proprioceptive sensory neurons also affects muscle spindle development. This influence is regulated by signaling between a splice variant of Neuregulin1 (Ig-Nrg1) containing an Ig domain that is selectively expressed by proprioceptive sensory neurons in the DRG, and its receptor, ErbB2, which is expressed by intrafusal fibers (Andrechek et al., 2002; Hippenmeyer et al., 2002; Leu et al., 2003; Cheret et al., 2013). Deletion of either Nrg1 or ErbB2 in mice causes reduced numbers of muscle spindles and limb coordination deficits (Andrechek et al., 2002; Hippenmeyer et al., 2002; Leu et al., 2003; Shneider et al., 2009; Cheret et al., 2013). Nrg1 has been shown to be a substrate for the membrane-bound protease, Beta-secretase 1 (Bace1), which is expressed in nervous tissues. Bace1 is an amyloid precursor protein (APP) cleavage enzyme that causes accumulation of amyloid β peptide, a hallmark of Alzheimer’s disease (Vassar et al., 1999). Deletion of Bace1 similarly causes a reduction in the number of muscle spindles (Cheret et al., 2013). In a transgenic mouse line that overexpresses Ig-Nrg1, muscle spindle numbers were increased by 50%. Bace1-deletion in these mice eliminates only the augmentation in spindle numbers, indicating that Bace1 cleavage of Nrg1 may be necessary for appropriate muscle spindle formation (Cheret et al., 2013). Interestingly, pharmacological inhibition of Bace1 or conditional deletion of Nrg1 in adult wild-type mice results in defects in muscle spindle numbers and locomotor deficits, suggesting that Bace1 activity is also required for muscle spindle maintenance (Cheret et al., 2013).

Taken together, proprioceptive innervation and the limb mesenchyme and muscle spindles have reciprocal influences during development. This bi-directional signaling between developing proprioceptive sensory neurons and peripheral tissues appear to be integral to the development of appropriate sensory-motor circuits.

(2) Molecular mechanisms directing central axon projections of proprioceptive sensory neurons

Proprioceptive sensory neurons project axons centrally to the spinal cord and invade the grey matter around E12.5 in mice (Ozaki and Snider, 1997). The axons avoid the dorsal spinal cord but project to the intermediate and ventral spinal cord. In contrast, cutaneous sensory neurons in the DRGs project axons directly to the dorsal spinal cord. Recent studies have shown that an array of different molecules—neurotrophic factors, transcription factors, protein kinases, and axon guidance molecules—all influence the central projections of proprioceptive sensory neurons within the spinal cord.

The growth factor neurotrophin 3 (NT3) is an essential trophic factor for proprioceptive sensory neurons, and its receptor TrkC is expressed specifically by proprioceptive sensory neurons in DRGs (Marmigere and Ernfors, 2007; Lallemend and Ernfors, 2012). Interestingly, previous studies show that NT3-TrkC signaling also plays a critical role in targeting axonal projections of proprioceptive sensory neurons in the spinal cord (Ernfors et al., 1994; Klein et al., 1994; Patel et al., 2003). NT3 or TrkC deletion in mice resulted in complete loss of all proprioceptive sensory neurons, rendering it impossible to examine how NT3-TrkC signaling affected proprioceptive axonal projections. However, in mice lacking both NT3 and BCL2-associated protein (Bax) deletion, which prevents cell death in DRG neurons, proprioceptive axons entered the spinal cord but terminated in the intermediate zone (Patel et al., 2003). The mechanism by which NT3-TrkC signaling controls proprioceptive axon projections is not understood, however one pathway currently being explored involves the transcription factor, ETS variant 1 (Etv1, also known as Er81), whose expression is induced by NT3-TrkC signaling. In NT3 mutants, expression of Etv1 is reduced in the DRGs, whereas ectopic NT3 in muscles in the transgenic mice induces Etv1 expression (Patel et al., 2003). Interestingly, overexpression of NT3 largely rescues the defects in proprioceptive axonal projections caused by Etv1 deletion. In Etv1 mutant mice, proprioceptive axons aberrantly terminate in the intermediate spinal cord, similar to what was observed in NT3/Bax mutant mice, although the Etv1 mutant phenotype appears to be weaker than that of NT3/Bax double mutant mice since some proprioceptive sensory neurons project axons to the ventral spinal cord, suggesting that NT3-TrkC signaling regulates proprioceptive axon projections in an Etv1-dependent and independent manner (Arber et al., 2000; Patel et al., 2003; Li et al., 2006; de Nooij et al., 2013).

Another downstream target of the NT3-TrkC signaling cascade, the synapses of amphids defective (SAD) kinases (SAD-A and –B in mammals), have also been shown to influence proprioceptive axonal projections. In SAD-A/B double mutant mice, proprioceptive axons stop in the intermediate zone similar to what was observed in NT3/Bax and Etv1 mutant mice (Lilley et al., 2013). SAD kinases are regulated positively by the NT3-TrkC signaling cascade through two mechanisms. First, NT3 increases protein levels of SAD kinases post-translationally through the Raf/MEK/ERK pathway, and second, NT3 upregulates SAD kinase activity via inactivation of the inhibitory c-terminal domain of SAD kinases (Lilley et al., 2013). Although it is unknown whether SAD kinases induce Etv1 expression in proprioceptive sensory neurons, the similarities in mutant phenotypes suggest that NT3-TrkC signaling may exert its effects on proprioceptive axonal projections through a pathway involving both SAD kinases and Etv1.

In addition to Etv1, another transcription factor, Runt-related transcription factor 3 (Runx3), is also essential for proprioceptive sensory neuron development (Inoue et al., 2002; Levanon et al., 2002; Chen et al., 2006; Kramer et al., 2006; Nakamura et al., 2008; Appel et al., 2016). In Runx3 mutant mice, proprioceptive sensory afferents failed to reach the ventral spinal cord (Inoue et al., 2002). Neuronal survival was unaffected in these mice (Inoue et al., 2002). A separate analysis of Runx3 mutant mice on a different genetic background, showed that Runx3 is critical for proprioceptive sensory neuron survival (Levanon et al., 2002). In chicks, however, loss- and gain-of-function experiments showed that Runx3 determines the dorsoventral termination points of both proprioceptive and cutaneous sensory neurons without affecting neuronal survival (Chen et al., 2006). Thus, the Runx3 transcription factor regulates survival and axonal projections of proprioceptive sensory neurons.

As mentioned earlier, cutaneous sensory neurons extend axons into the dorsal region of the spinal cord, whereas proprioceptive sensory axons avoid the dorsal area and project to the intermediate and ventral spinal cord regions. Recently, we discovered that repulsive signaling between the axon guidance molecule, semaphorin 6D (Sema6D), and its receptor, plexin A1 (PlexA1) repel axons of proprioceptive sensory neurons away from the dorsal spinal cord (Yoshida et al., 2006; Leslie et al., 2011). Knocking out Sema6D or PlexA1 results in proprioceptive axons invading the dorsal spinal cord region (Yoshida et al., 2006; Leslie et al., 2011). These aberrant proprioceptive axon shafts introduce ectopic oligodendrocytes into the dorsal area, inhibiting synapse formation of cutaneous sensory neurons with spinal interneurons (Yoshida et al., 2006; Leslie et al., 2011). Despite these abnormalities, PlexA1 mutant mice do not show obvious defects in monosynaptic sensory-motor connections by electrophysiological assays (Leslie et al., 2011). Thus Sema6D-PlexA1 signaling in mice does not appear to be involved in sensory-motor synaptogenesis but is crucial for proprioceptive axon shaft positioning in the spinal cord which is required for proper neural circuit formation (Yoshida, 2012). These findings also suggest that oligodendrocytes may be involved in shaping synapse formation in the central nervous system in wild-type mice.

(3) Synaptic specificity and synapse formation of monosynaptic sensory-motor connections during development

It has long been established that Ia proprioceptive afferents form specific monosynaptic connections with particular motor neuron pools (Eccles et al., 1957). Therefore, these circuits have become model systems for understanding the molecular mechanisms underlying synaptic specificity.

Proprioceptive sensory afferents form monosynaptic connections with specific motor neuron targets that innervate either the same muscle (homonymous connections) or related muscles (heteronymous connections). In mice, monosynaptic connections are formed earlier than E17 and were believed to be established independent of neuronal activity (Mendelson and Frank, 1991; Mears and Frank, 1997). However, a recent study showed that heteronymous monosynaptic sensory-motor connections for the related muscle pair, tibialis anterior (TA, ankle flexor muscle) and extensor digitorum longus (EDL, toe extensor muscle), are coordinated through a sensory neuron activity-dependent process (Mendelsohn et al., 2015). In early postnatal mice, TA sensory neurons have weak heteronymous monosynaptic connections with EDL motor neurons and strong homonymous monosynaptic connections with TA motor neurons. Blocking proprioceptive sensory neuron activity enhances the number and density of heteronymous connections without affecting homonymous connections (Mendelsohn et al., 2015). These data suggests that heteronymous (but not homonymous) connections are coordinated by sensory inputs in an activity-dependent manner.

A recent study revealed that the location of motor neurons along the dorsoventral axis plays a key role in establishing monosynaptic sensory-motor specificity (Surmeli et al., 2011; Figure 2). Within the ventral spinal cord, each motor neuron pool is located in stereotypic dorsoventral and mediolateral positions which are determined, at least in part, by the transcription factor, Forkhead box protein P1 (FoxP1) (Dasen et al., 2008; Rousso et al., 2008; Surmeli et al., 2011). In Foxp1 conditional mutant mice, the dorsoventral positions of motor neurons are disrupted causing intermingling of motor neuron pools. Sensory-motor specificity is also perturbed (Surmeli et al., 2011). Interestingly, the sensory axons innervating each muscle in FoxP1 mutants preferentially target motor neuron pools occupying the wild-type dorsoventral positions in the ventral spinal cord, rather than following specific motor neurons to their new, altered locations (Surmeli et al., 2011).

Figure 2.

Figure 2

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Molecular mechanisms underlying the formation of monosynaptic sensory-motor connections

In wild type mice (left), flexor Ia proprioceptive sensory (red) and extensor Ia proprioceptive sensory neurons (blue) connect to flexor motor neurons (MNs, red) and extensor MNs (blue), respectively. Sensory-motor connection specificity is determined by MN position-dependent (middle) and MN position-independent mechanisms (right). Abnormal MN positioning causes inappropriate sensory-motor connections in FoxP1 mutants (middle). In Sema3e and PlexD1 mutants (right), the absence of repulsion signaling causes inappropriate connections without MN position defects.

Sensory-motor specificity is also influenced by motor neuron-derived molecules such as the repellant molecule semaphorin 3E (Sema3E) and its receptor plexin D1 (PlexD1) (Figure 2). Sema3E-PlexD1 signaling has been shown to control the specificity of monosynaptic sensory-motor connections (Fukuhara et al., 2013). Motor neurons innervating the gluteus (hip extensor) muscle express Sema3E while PlexD1 is expressed by Ia sensory neurons innervating the hamstrings (hip/knee flexor muscle). The Ia proprioceptive sensory neurons in the hamstrings muscle do not typically form monosynaptic connections with gluteus motor neurons in wild-type mice, however, deletion of either Sema3E or PlexD1 results in direct sensory-motor synapse formation, indicating that under normal circumstances, the Sema3E-PlexD1 repulsion mechanism is necessary to prevent aberrant contacts between Ia proprioceptive sensory neurons and gluteus motor neurons. In Sema3E mutant mice, positiosn and dendritic patterns of motor neurons are not altered, indicating that Sema3E-PlexD1 regulates sensory-motor specificity, independent of motor neuron position (Fukuhara et al., 2013). Sema3E-PlexD1 signaling also precludes the formation of monosynaptic connections by cutaneous maximus (Cm) motor neurons in the cervical spinal cord (Pecho-Vrieseling et al., 2009). Although most proprioceptive sensory neurons form monosynaptic connections with motor neurons, those innervating the Cm muscle do not synapse with Cm motor neurons (Vrieseling and Arber, 2006; Pecho-Vrieseling et al., 2009) due likely to Sema3E being expressed in Cm motor neurons and PlexD1 being expressed by Cm proprioceptive sensory neurons (Pecho-Vrieseling et al., 2009). Knocking out either Sema3E or PlexD1 in mice results in monosynaptic connections forming between Cm proprioceptors and Cm motor neurons (Pecho-Vrieseling et al., 2009). Thus, both at cervical and lumbar levels of the spinal cord, Sema3E-PlxnD1 signaling prevents atypical sensory-motor connections.

Considering that there are over 50 types of hindlimb motor neuron pools and individual motor neuron pool has own specific inputs from particular proprioceptive sensory neurons, a wide array of molecules likely aid in the establishment of monosynaptic sensory-motor circuits (Vanderhorst and Holstege, 1997). For example, members of the cadherin superfamily of adhesion molecules are required for several types of neuronal connections (Takeichi, 2007). In the spinal cord, different type II-cadherin family genes are expressed by different subsets of motor neurons that control a variety of muscles (Price et al., 2002). Another branch of the cadherin superfamily, protocadherins (Pcdhs), are known to be involved in dendritic self-avoidance, and thus, are also good candidates for controlling sensory-motor specificity (Lefebvre et al., 2012; Kostadinov and Sanes, 2015). Since Pcdh mutant mice show upregulation of Ia afferent terminal density, Pcdhs may suppress specific proprioceptive sensory inputs to motor neurons (Prasad and Weiner, 2011; Chen et al., 2012; Hasegawa et al., 2016). Further studies on members of the cadherin superfamily as well as other families of cell surface and signaling molecules will contribute to our understanding of the development of synaptic specificity.

After Ia proprioceptive sensory afferents find their appropriate target motor neurons, the synapses mature. A recent study in mice showed that loss of Cdc42, a small GTPase, caused defects in synapse formation in monosynaptic sensory-motor connections (Imai et al., 2016b). Although Cdc42 in post-synaptic neurons has been shown to control synapse formation in other regions of the CNS, knocking out Cdc42 in motor neurons (the post-synaptic neurons in monosynaptic sensory-motor connections) did not affect sensory-motor synaptogenesis (Irie and Yamaguchi, 2002; Murakoshi et al., 2011; Kim et al., 2014; Hedrick et al., 2016). Cdc42 was deleted from sensory neurons (the pre-synaptic neurons), proprioceptive sensory axons appropriately reached the ventral spinal cord and formed monosynaptic connections with their proper motor neuron targets, however, the numbers of contacts were reduced (Imai et al., 2016b). These findings revealed that Cdc42 in proprioceptive sensory neurons does not affect synaptic specificity, but is required for synapse formation. The downstream targets of Cdc42 that ultimately drive synaptogenesis in proprioceptive sensory neurons are undetermined, but some have proposed that molecules involved in cytoskeletal regulation in dendrites, such as actin, are likely candidates (Hedrick and Yasuda, 2017).

Taken together, proprioceptive sensory afferents find their specific target motor neurons through motor neuron-positioning and cues from guidance molecules. Although thus far, only repulsive molecules have been found that influence monosynaptic sensory-motor specificity, it is plausible that attractant molecules also participate in the process. After proprioceptive afferents form initial contacts with their target motor neurons, the synapse formation, in part, through cytoskeletal regulation by intracellular signaling molecules such as Cdc42.

(4) Maintenance of monosynaptic sensory-motor circuits

After monosynaptic sensory-motor connections are established during embryogenesis, these circuits need to be maintained throughout an animal’s lifetime. Recent studies have begun to address mechanisms underlying the support and maintenance of monosynaptic sensory-motor circuits.

In general, neural circuit maintenance can be disrupted by disease and aging. For example, in amyotrophic lateral sclerosis (ALS), a motor neuron disease whereby accumulation of misfolded superoxide dismutase 1 (SOD1) proteins in motor neurons causes neuronal death, recent studies show that sensory neurons are also affected in human patients with ALS and in an ALS mouse line (Hammad et al., 2007; Pugdahl et al., 2007; Sabado et al., 2014; Vaughan et al., 2015). In the ALS mouse model, accumulation of misfolded SOD1 proteins in proprioceptive sensory neurons and degeneration of spiral structures in proprioceptive sensory endings are observed in 90–120 day-old mice without noticeable impact on neuronal survival (Sabado et al., 2014; Vaughan et al., 2015). In addition to peripheral defects, sensory inputs on motor neurons are reduced (Vaughan et al., 2015). Similar structural degeneration of proprioceptive sensory endings occurs during the normal aging process in wild-type mice (11–15 month-old), suggesting that the maintenance program in sensory neurons can be disrupted similarly by disease and aging (Vaughan et al., 2016). Spinal muscular atrophy (SMA) is another disease affecting neurons. A recent study demonstrated that monosynaptic sensory-motor circuits are not maintained in a model SMA mouse line (Mentis et al., 2011). In SMA mice, sensory inputs on motor neurons seem to be normally formed at P0, but their connections are decreased by P4. Additionally, reduction of sensory inputs seems to cause motor neuron dysfunction, suggesting that proprioceptive sensory neurons play a critical role in protecting motor neurons against the cell death that is a hallmark of SMA disease (Mentis et al., 2011; Fletcher et al., 2017).

In addition to disease and aging, sensory-motor maintenance appears to be influenced by the extracellular molecule NT3. Muscle spindle-specific NT3 mutant mice as well as muscle spindle defect mice (Egr3 and Erbb2 mutants) show reduced strength in monosynaptic sensory-motor connections compared to control mice but only in later postnatal stages (Chen et al., 2002; Shneider et al., 2009). This suggests that spindle–derived NT3 is important for the maturation and/or maintenance of sensory-motor connections rather than their initiation or specification. Therefore, these studies indicate that muscle spindles and/or spindle-derived factors such as NT3 may play prominent roles in regulating sensory-motor strength and maintenance.

Recent studies have revealed a molecular mechanism underlying the maintenance of monosynaptic sensory-motor circuits in wild-type mice (Imai et al., 2016a; O’Toole et al., 2017). Loss of Dicer, an RNase essential for processing microRNAs (miRNAs), in proprioceptive sensory neurons causes sensory ataxia (Imai et al., 2016a; O’Toole et al., 2017). Proprioceptive sensory neuron-specific Dicer deletion in mice does not affect specificity or formation of monosynaptic sensory-motor connections in early postnatal mice, however, after postnatal day 21, proprioceptive sensory neurons lose identity markers such as central and peripheral projections, and typical gene expression patterns, suggesting that Dicer is essential for maintenance rather than initiation of synaptic contacts (Imai et al., 2016a; O’Toole et al., 2017). Indeed, in these mutant mice, some mature miRNAs are downregulated and entire mRNA expression profiles are changed, indicating that Dicer-mediated miRNA maturation helps to maintain proprioceptor identities as defined by transcription factors, signaling molecules, channels and other cellular proteins (Imai et al., 2016a; O’Toole et al., 2017). For example, miRNA mir-127 is highly expressed in all of DRG neurons and contains target sequences for F-box only protein2 (Fbxo2) which negatively regulates synapse formation and/or maintenance in hippocampus, suggesting that mir-127 mediated Fbxo2 downregulation could be involved in sensory-motor maintenance (Atkin et al., 2015; Imai et al., 2016a). Future studies will reveal roles of miRNAs and miRNA-related gene regulation on the maintenance of these and other neural circuits, and their possible functions in disease and aging.

Summary and future directions

In this article, we reviewed the recent molecular advancements in the field of sensory-motor circuit development and maintenance. Contemporary studies have revealed how proprioceptive sensory afferents project axons to the spinal cord, how they form appropriate connections with particular motor neuron targets, how sensory-motor synapses mature, and how monosynaptic sensory-motor circuits are maintained in mice. However, many questions still remain. For example, what drives the different proprioceptive sensory afferents to either synapse directly with motor neurons (in the case of group Ia/II proprioceptive sensory neurons) or synapse on interneurons that then connect with motor neurons (group Ib proprioceptors). Although several proprioceptor-specific molecules such as TrkC, Etv1, Parvalbumin and Runx3 have been shown to be expressed in all proprioceptive sensory neurons, unique molecular markers for different proprioceptor subtypes have yet to be identified (de Nooij et al., 2013; Sonner et al., 2017). Single-cell gene expression studies (Chiu et al., 2014; Usoskin et al., 2015) paired with electrophysiological subtyping experiments (Vincent et al., 2017) could identify genes specific to different classes of proprioceptors. Also worthy of note - proprioceptive sensory neurons at cervical levels project additional axons into the external cuneate nucleus (ECN) in the medulla (Niu et al., 2013). Functional analysis of those axons will be another interesting avenue of exploration. Finally, compared to monosynaptic sensory-motor connections, the molecular mechanisms underlying synaptogenesis between proprioceptive sensory neurons and spinal interneurons in disynaptic connections remain virtually unknown. As recent studies uncover more about the molecular identities of different interneuron subtypes (Goulding, 2009; Bikoff et al., 2016; Gabitto et al., 2016; Kiehn, 2016), classification of each subtype and subsequent mapping of proprioceptor-interneuron circuits will help us to better understand the function and development of disynaptic sensory-motor connections within the spinal cord (Bikoff et al., 2016; Gabitto et al., 2016).

Acknowledgments

We thank to D. Ladle (Wright State University) for providing comments on the manuscript.

Funded by National Institute of Neurological Disorders and Stroke: RO1NS093002 and RO1NS100772

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