Muscle-type Identity of Proprioceptors Specified by Spatially Restricted Signals from Limb Mesenchyme

Poliak, Sebastian; Norovich, Amy L.; Yamagata, Masahito; Sanes, Joshua R.; Jessell, Thomas M.

doi:10.1016/j.cell.2015.12.049

Cited by 52 publications

(76 citation statements)

References 48 publications

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“…In this study, proprioceptive neuron specialization was neither affected by the MNs nor by muscle genetic ablation, pointing instead towards the contribution of mesenchymal cells. The identity of the regionalized mesenchyme-derived signals regulated by Lmx1b patterning activity, also remains unknown [88].…”

Section: Mesenchymal Fat1 Controls CM Muscle Growth and Impacts Mn Dementioning

confidence: 99%

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Helmbacher

2017

Preprint

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Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis, and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissuespecific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation, but tightly associated with elongating axons of its partner motor neurons. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool.Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets including the CM-innervating pool. We identify mesenchyme-derived connective tissue as a cell type in which Fat1 activity is required for the non-cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types. Author summaryBuilding neuromuscular circuits involves a tight control of morphogenetic and regulatory events driving muscle and motor neuron development. Alterations of these processes can lead to congenital abnormalities or be at the root of human pathologies. Here, we show that the mouse Fat1 cadherin gene, a developmental regulator of muscle morphogenesis, coordinates the coupling between muscle and neuronal development by playing complementary functions in mesenchyme, muscles and motor neurons. These findings may be particularly relevant for Facioscapulohumeral dystrophy (FSHD), a muscle disease affecting subgroups of muscles in the face and shoulder, which is thought to involve developmental alterations. Although FSHD is known to traditionally result from a complex combination of genetic defects, the link between the altered molecular mechanisms and the specific set of muscles affected in patients is still poorly understood. Fat1 deficiency in mice causes phenotypes reminiscent of FSHD symptoms. Furthermore, pathogenic FAT1 variants have been identified in patients with FSHD-like phenotypes, and FAT1 expression is deregulated in classical forms of FSHD. Thus, a better understanding of the developmental functions of Fat1 could guide research on FSHD pathogenesis. In particular, by showing that Fat1 disru...

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Section: Mesenchymal Fat1 Controls CM Muscle Growth and Impacts Mn Dementioning

confidence: 99%

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Helmbacher

2017

Preprint

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“…During locomotion, the CNS continuously elaborates the information coming from proprioceptors, a myriad of sensors (Poliak et al . ) located both in muscles (group Ia/II muscle spindles) and tendons (group Ib Golgi tendon organs, GTOs). It is well known that the loss of proprioceptive feedback may severely affect the motor function in mammals and is a symptom commonly associated with numerous neurological and orthopaedic conditions (Peterka, ; Konczak et al .…”

Section: Introductionmentioning

confidence: 99%

“…For instance, the ability to sense the position of own body parts in relation to the surrounding environment and the body itself, called proprioception, is of clear importance (Pearson, 1995). During locomotion, the CNS continuously elaborates the information coming from proprioceptors, a myriad of sensors (Poliak et al 2016) located both in muscles (group Ia/II muscle spindles) and tendons (group Ib Golgi tendon organs, GTOs). It is well known that the loss of proprioceptive feedback may severely affect the motor function in mammals and is a symptom commonly associated with numerous neurological and orthopaedic conditions (Peterka, 2002;Konczak et al 2009;Akay et al 2014;Fling et al 2014;Aman et al 2015;.…”

Section: Introductionmentioning

confidence: 99%

Modular organization of murine locomotor pattern in the presence and absence of sensory feedback from muscle spindles

Santuz

Akay

Mayer

et al. 2019

The Journal of Physiology

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Key points Locomotion on land and in water requires the coordination of a great number of muscle activations and joint movements. Constant feedback about the position of own body parts in relation to the surrounding environment and the body itself (proprioception) is required to maintain stability and avoid failure. The central nervous system may follow a modular type of organization by controlling muscles in orchestrated groups (muscle synergies) rather than individually. We used this concept on genetically modified mice lacking muscle spindles, one of the two main classes of proprioceptors. We provide evidence that proprioceptive feedback is required by the central nervous system to accurately tune the modular organization of locomotion. Abstract For exploiting terrestrial and aquatic locomotion, vertebrates must build their locomotor patterns based on an enormous amount of variables. The great number of muscles and joints, together with the constant need for sensory feedback information (e.g. proprioception), make the task of controlling movement a problem with overabundant degrees of freedom. It is widely accepted that the central nervous system may simplify the creation and control of movement by generating activation patterns common to muscle groups, rather than specific to individual muscles. These activation patterns, called muscle synergies, describe the modular organization of movement. We extracted synergies through electromyography from the hind limb muscle activities of wild‐type and genetically modified mice lacking sensory feedback from muscle spindles. Muscle spindle‐deficient mice underwent a modification of the temporal structure (motor primitives) of muscle synergies that resulted in diminished functionality during walking. In addition, both the temporal and spatial (motor modules) components of synergies were severely affected when external perturbations were introduced or when animals were immersed in water. These findings show that sensory feedback from group Ia/II muscle spindles regulates motor function in normal and perturbed walking. Moreover, when group Ib Golgi tendon organ feedback is lacking due to enhanced buoyancy, the modular organization of swimming is almost completely compromised.

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“…In contrast, ΔR1,2 mice expressing only low Runx3 levels at E12.5 showed a later gain of Runx3 expression and exhibited no ataxia, although they did display locomotion defects in home cage and beam tests. Given that normal locomotion requires proper function of extensor and flexor muscles, which form connections with distinct TrkC subtypes (Poliak et al 2016), the fact that ΔR1,2 mice are not ataxic supports the notion of functional heterogeneity within this R3-only TrkC neuron subgroup. Moreover, given that R3 is less conserved than R1 (Supplemental Table S2), this subgroup may be associated with a phylogenetically more recent function of TrkC neurons.…”

Section: Combinatorial Re Cross-talk Regulates Runx3 In Different Trkmentioning

confidence: 81%

“…Using single-cell RNA-seq, two proprioceptive subtypes were detected in adult mouse DRGs (Usoskin et al 2015). It was also reported that mesenchymal signals expressed in restricted dorsoventral and proximodistal domains of the developing limb are essential for endowing muscle-type identity to two distinct proprioceptive subtypes, marked by the expression of either Cdh13, Sema5, or Crtac1 (Poliak et al 2016).…”

Section: Combinatorial Re Cross-talk Regulates Runx3 In Different Trkmentioning

confidence: 97%

An ensemble of regulatory elements controls Runx3 spatiotemporal expression in subsets of dorsal root ganglia proprioceptive neurons

et al. 2016

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The Runx3 transcription factor is essential for development and diversification of the dorsal root ganglia (DRGs) TrkC sensory neurons. In Runx3-deficient mice, developing TrkC neurons fail to extend central and peripheral afferents, leading to cell death and disruption of the stretch reflex circuit, resulting in severe limb ataxia. Despite its central role, the mechanisms underlying the spatiotemporal expression specificities of Runx3 in TrkC neurons were largely unknown. Here we first defined the genomic transcription unit encompassing regulatory elements (REs) that mediate the tissue-specific expression of Runx3. Using transgenic mice expressing BAC reporters spanning the Runx3 locus, we discovered three REs-dubbed R1, R2, and R3-that cross-talk with promoter-2 (P2) to drive TrkC neuron-specific Runx3 transcription. Deletion of single or multiple elements either in the BAC transgenics or by CRISPR/Cas9-mediated endogenous ablation established the REs' ability to promote and/or repress Runx3 expression in developing sensory neurons. Our analysis reveals that an intricate combinatorial interplay among the three REs governs Runx3 expression in distinct subtypes of TrkC neurons while concomitantly extinguishing its expression in non-TrkC neurons. These findings provide insights into the mechanism regulating cell type-specific expression and subtype diversification of TrkC neurons in developing DRGs.

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Muscle-type Identity of Proprioceptors Specified by Spatially Restricted Signals from Limb Mesenchyme

Cited by 52 publications

References 48 publications

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Modular organization of murine locomotor pattern in the presence and absence of sensory feedback from muscle spindles

An ensemble of regulatory elements controls Runx3 spatiotemporal expression in subsets of dorsal root ganglia proprioceptive neurons

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