γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons

Abstract

SummaryLight touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions. The Pcdhgc3 isoform mediates homophilic interactions between sensory axons and spinal cord neurons to promote synapse formation in vivo, and is sufficient to induce postsynaptic specializations in vitro. Moreover, loss of Pcdhgs and somatosensory synaptic inputs to the dorsal horn lead to fewer corticospinal synapses onto dorsal horn neurons. These findings reveal essential roles for Pcdhg isoform diversity in somatosensory neuron synapse formation, peripheral axonal branching, and step-wise assembly of central mechanosensory circuitry.

Touch receptor end-organ innervation and function requires sensory neuron expression of the transcription factor Meis2

“…This finding was confirmed using a series of vibration steps of increasing amplitudes again demonstrating decreased firing in response to 25 Hz vibration stimuli (Figure 6C). Thus, the functional deficits in RA-LTMRs correlate well with the defects in LTMR cutaneous projections we observed in Isl1 Interestingly, Meis2 inactivation seems to interfere with the embryonic expression of many members of the protocadherin family, and the protocadherin γ cluster (Pcdhg) in particular has recently been highlighted as essential for building central and peripheral LTMRs innervation and synapses and establish proper peripheral target-field innervation and touch sensation (23).…”

“…Thus, the gene list associated with the GOterm “synapse” strongly links LTMR neurotransmitter type of synapses, their dysfunction in mouse model of ASD ( 24 , 25 ) and the association of Meis2 with ASD ( 26 , 65 , 74 ). Interestingly, Meis2 inactivation seems to interfere with the embryonic expression of many members of the protocadherin family, and the protocadherin γ cluster (Pcdhg) in particular has recently been highlighted as essential for building central and peripheral LTMRs innervation and synapses and establish proper peripheral target-field innervation and touch sensation ( 23 ).…”

“…For instance, the functions of specification factors or terminal selectors, like Maf, Shox2, Runx3, Pea3 and ER81 have been functionally implicated in LTMR segregation (8,9,(19)(20)(21)(22). Whereas the specific function of adhesion molecules in shaping the assembly of touch circuitry is being unraveled (23), the transcriptional control of target cell innervation within the skin and of the establishment of specialized peripheral end-organ complexes is less understood. Recent advances in the understanding of Autism Spectrum Disorder (ASD) suggest that centrally affected neurons in ASD and LTMRs share transcriptional programs regulating late neuronal differentiation (24,25).…”

Follicle-innervating Aδ-low threshold mechanoreceptors organize through a population-dependent mechanism

“…Similarly, recent work has shown that the GPI-linked receptor Netrin-G1 is required in LTMRs for the proper maturation of terminal endings around hair follicles, but not for terminal axon branching or receptive field size (Meltzer et al, 2022b preprint). In contrast, ɣ-Protocadherins are important for the peripheral branching and innervation of non-guard hair follicles by Aβ-LTMRs, but not for the maturation of LLEs (Meltzer et al, 2022a preprint). Together, these data suggest that the initial innervation of hair follicles and the morphological maturation of their terminal endings are distinct events regulated by different molecular pathways.…”

“…Together, these data suggest that the initial innervation of hair follicles and the morphological maturation of their terminal endings are distinct events regulated by different molecular pathways. Interestingly, terminal Schwann cells are the source for ligands/binding partners for both Netrin-G1 and ɣ-Protocadherins in LTMRs, demonstrating that they play a critical role in regulating hair follicle innervation (Meltzer et al, 2022a preprint; Meltzer et al, 2022b preprint).…”