Axonal projections of mechanoreceptive dorsal root ganglion neurons depend on Ret

Abstract

SUMMARYEstablishment of connectivity between peripheral and central organs is essential for sensory processing by dorsal root ganglion (DRG) neurons. Using Ret as a marker for mechanoreceptive DRG neurons, we show that both central and peripheral projections of mechanoreceptive neurons are severely impaired in the absence of Ret. Death of DRG neurons in Ret-deficient mice can be rescued by eliminating Bax, although their projections remain disrupted. Furthermore, ectopic expression of the Ret ligand neurturin, but not Gdnf, in the spinal cord induces aberrant projection of mechanoreceptive afferents. Our results demonstrate that Ret expression in DRG neurons is crucial for the neurturin-mediated formation of precise axonal projections in the central nervous system.

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

“…The glabrous footpad, which receives dense cutaneous nociceptive and mechanoceptive sensory innervation, was examined using peripherin (Prph) and heavy chain neurofilament (NF-H) immunohistochemistry (Honma et al, 2010). Cutaneous sensory innervation of footpads was profoundly abnormal in Wnt1-cKO mice where Prph+ and NF-H+ axon innervation was reduced to 6.8% and 11.0%, respectively (n=2 or 3 mice and >40 tissue sections analyzed per genotype, P<0.0001, Student's t-test) (Fig.…”

c-Maf Is Required for the Development of Dorsal Horn Laminae III/IV Neurons and Mechanoreceptive DRG Axon Projections

“…In situ hybridization results showed that this was indeed the case. Because the expression of MafA, the early wave of Ret (Ret ϩ /TrkA Ϫ ), and Ret coreceptor GFR␣2 all can be used to indicate the development of the MafA ϩ / Ret ϩ /GFR␣2 ϩ LTMs (Bourane et al, 2009;Luo et al, 2009;Honma et al, 2010), we quantified the numbers of cells expressing GFR␣2, MafA, and early Ret (Ret ϩ /TrkA Ϫ ) in the DRG of control and c-Maf deletion mice at E18.5. We found that a reduction of 55%, 70%, and 50% in the number of GFR␣2 ϩ , MafA ϩ , and Ret ϩ /TrkA Ϫ DRG neurons occurred in c-Maf Ϫ/ Ϫ mice at E18.5 (Fig.…”

“…Immunostaining of VGLUT1 was performed on spinal cord from c-Maf deletion mice and control mice. Because Ret expression in the laminae III/IV can be used for labeling MafA (Bourane et al, 2009;Luo et al, 2009;Honma et al, 2010), we performed immunostaining of Ret in c-Maf deletion mice as well. Immunostaining of TrkA and parvalbumin, the molecular markers for labeling projections of nociceptors and proprioceptors, was performed on spinal cord sections adjacent to those used for VGLUT1 staining.…”

“…Recent studies demonstrate that early-born Ret ϩ sensory neurons are RA mechanoreceptors, whose peripheral nerve terminals are associated with Meissner corpuscles, longitudinal lanceolate endings, and Pacinian corpuscles (Bourane et al, 2009;Luo et al, 2009;Honma et al, 2010). Pacinian corpuscles are the only LTM peripheral endings, majority of which (91.7%) are innervated by early Ret ϩ fibers, and are completely absent in the periosteum membrane of the fibula of Ret deletion mice at P14 (Luo et al, 2009).…”

“…Furthermore, transcription factor Shox2 (short stature homeobox2) is required for proper development of TrkB-expressing mechanosensory neurons (Scott et al, 2011). Last, three studies have found that Ret signaling was required for the specification of MafA ϩ /Ret ϩ /GFR␣2 ϩ low-threshold mechanoreceptor (LTMs) (Bourane et al, 2009;Luo et al, 2009;Honma et al, 2010). The finding that the phenotypes of central and peripheral projections of LTMs in MafA deletion mice do not recapitulate those observed in Ret mutants indicated that an unknown transcription factor may control the differentiation of MafA ϩ /Ret ϩ /GFR␣2 ϩ LTMs (Bourane et al, 2009).…”