Molecular Identification of Rapidly Adapting Mechanoreceptors and Their Developmental Dependence on Ret Signaling

Luo, Wenqin; Enomoto, Hideki; Rice, Frank L.; Milbrandt, Jeffrey; Ginty, David D.

doi:10.1016/j.neuron.2009.11.003

Cited by 210 publications

(360 citation statements)

References 55 publications

(93 reference statements)

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“…These sensory abnormalities may be comparable with neuropathic pain in the somatosensory system. We found that endogenous GDNF induced basal firing at low frequencies ϳ0.1 Hz or less in touch-sensitive or RA mechanoreceptive fibers, which are characterized by the expression of RET during a developmental period (Bourane et al, 2009;Luo et al, 2009). We confirmed that GDNF and GFR␣1 were present in Meissner corpuscles.…”

Section: Basal Firing In Sensory Nervessupporting

confidence: 72%

“…Because the basal firing was found in touch-sensitive or rapidly adapting (RA) mechanoreceptive fibers, it may be produced by a mechanism specific to RA mechanoreceptive fibers. RA mechanoreceptive neurons in the dorsal root ganglia or trigeminal ganglia are characterized by the expression of the receptor tyrosine kinase RET during a certain developmental period (Bourane et al, 2009;Luo et al, 2009). RET is a component of the GDNF family receptors.…”

Section: Somatic Cortical Potentiation After Peripheral Nerve Cuttingmentioning

confidence: 99%

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Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

Komagata

Chen²,

Suzuki³

et al. 2011

J. Neurosci.

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We tested a hypothesis that the spinal plasticity induced within a few hours after nerve injury may produce changes in cortical activities and an initial phase of neuropathic pain. Somatosensory cortical responses elicited by vibratory stimulation were visualized by transcranial flavoprotein fluorescence imaging in mice. These responses were reduced immediately after cutting the sensory nerves. However, the remaining cortical responses mediated by nearby nerves were potentiated within a few hours after nerve cutting. Nerve injury induces neuropathic pain. In the present study, mice exhibited tactile allodynia 1-2 weeks after nerve injury. Lesioning of the ipsilateral dorsal column, mediating tactile cortical responses, abolished somatic cortical responses to tactile stimuli. However, nontactile cortical responses appeared in response to the same tactile stimuli within a few hours after nerve injury, indicating that tactile allodynia was acutely initiated. We investigated the trigger mechanisms underlying the cortical changes. Endogenous glial cell line-derived neurotrophic factor (GDNF), found in the Meissner corpuscles, induced basal firing ϳ0.

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Section: Basal Firing In Sensory Nervessupporting

confidence: 72%

Section: Somatic Cortical Potentiation After Peripheral Nerve Cuttingmentioning

confidence: 99%

Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

Komagata

Chen²,

Suzuki³

et al. 2011

J. Neurosci.

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“…Within the central nervous system, we analyzed the brain, as signaling via Ret is important for the survival of central noradrenergic neurons and dopaminergic neurons in the ventral midbrain, as well as the spinal cord, where GDNF/ GFR␣1/Ret signaling is critical for axon guidance into the hind limbs and survival of ␥ motor neurons (16 -21). In the peripheral nervous system, we analyzed sensory neurons of the dorsal root ganglia (DRG), where neurturin/GFR␣2/Ret signaling is important for the survival and maintenance of mechanoreceptors during development (22,23). Additionally, shortly after birth, a subclass of nociceptors transition from being TrkApositive to expressing GFR␣1/Ret to support the development and survival of nonpeptidergic nociceptors (24 -26).…”

Section: Exon Skipping Creates Large Deletions In the Extracellularmentioning

confidence: 99%

Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction

Gabreski

Vaghasia

Novakova

et al. 2016

Journal of Biological Chemistry

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Rearranged during transfection (RET), a receptor tyrosine kinase that is activated by the glial cell line-derived neurotrophic factor family ligands (GFLs), plays a crucial role in the development and function of the nervous system and additionally is required for kidney development and spermatogenesis. RET encodes a transmembrane receptor that is 20 exons long and produces two known protein isoforms differing in C-terminal amino acid composition, referred to as RET9 and RET51. Studies of human pheochromocytomas identified two additional novel transcripts involving the skipping of exon 3 or exons 3, 4, and 5 and are referred to as RET ⌬E3 and RET ⌬E345 , respec- higher baseline autophosphorylation, specifically on the catalytic tyrosine, Tyr 905 , and also on one of the most important signaling residues, Tyr 1062 . These data provide the first evidence for a physiologic role of these isoforms in RET pathway function.RET is a receptor tyrosine kinase that is critical for kidney morphogenesis, spermatogenesis, and development of the nervous system (1-4). RET is activated by a family of four growth factors known as the glial cell line-derived neurotrophic factor (GDNF) 2 family ligands (GFLs), which includes GDNF, neurturin, artemin, and persephin (1). Each GFL binds to one of four cognate glycosylphosphatidylinositol-anchored co-receptors known as the GDNF family receptor ␣s (GFR␣s) (2, 5). The GFL-GFR␣ complex binds to RET, inducing RET dimerization and subsequent autophosphorylation on multiple tyrosine residues within the intracellular tyrosine kinase domain. This enhances tyrosine kinase activity and initiates the association of adaptor proteins and enzymes that trigger multiple second messenger cascades (6). The presence of two major Ret isoforms, RET9 and RET51, has been extensively described in the literature, and a third isoform, RET43, has also been observed in humans (7-9). Ret is 20 exons long, and Ret9 and Ret51 transcripts differ in alternative splicing of intron 19. Intron 19 in the Ret51 transcript is excised properly, whereas, in the Ret9 transcript, the intron is retained, changing the reading frame and inserting a premature stop codon into the amino acid sequence. This creates a unique nine-amino acid C-terminal sequence for RET9 and a unique 51-amino acid C-terminal sequence for RET51. Interestingly, these two different isoforms display marked differences in their degradation and function (7, 10, 11).Three additional Ret transcripts have been reported in various tumor sources as well as adult human tissues (12). These novel transcripts are a product of exon skipping in the 5Ј region of RET, which encodes for the extracellular domain of the protein. Skipping of exons 3 (RET ⌬E3 ) or exons 3, 4 and 5 (RET ⌬E345) gives rise to transcripts that encode for full-length Ret proteins but with deletions in the extracellular domain, specifically cadherin-like domain 1 (CLD1) or CLD1-3, respectively. These deletions are hypothesized to change the extracellular domain structure as well as binding to GFL-GFR...

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“…Ret expression appears early during development of mechanoreceptors, and in the absence of Ret, cutaneous mechanoreceptive end-organs are underdeveloped and Pacinian corpuscles are absent. 15,16 The transcription factor short stature homeobox 2 (Shox2) promotes TrkB expression in mechanoreceptors, and Shox2 is required for formation of most TrkB+ neurons. Consistent with this, Shox2 mutants have a deficit in a subset of mechanoreceptors that terminate in Meissner corpuscles and Merkel cells, and light touch sensation is strongly impaired.…”

Section: Molecular Mechanisms Of Mechanoreceptor Developmentmentioning

confidence: 99%

“…Interestingly, c-Maf is essential for appropriate expression of Ret, and the morphology of rapidly adapting mechanoreceptors in Ret mutant mice resemble those observed in c-Maf mutants. 15,16,20 Several deregulated genes encode potassium channels; among these Kcnq4 is already known to affect firing properties of rapidly adapting mechanoreceptors and contributes to the changes observed in c-Maf mutants. 20,23 MafA is co-expressed with c-Maf in rapidly adapting mechanoreceptors and the two closely related factors might act redundantly.…”

mentioning

confidence: 99%