Uncoupling of Molecular Maturation from Peripheral Target Innervation in Nociceptors Expressing a Chimeric TrkA/TrkC Receptor

Neurotrophins and their receptors control a number of cellular processes, such as survival, gene expression and axonal growth, by activating multiple signalling pathways in peripheral neurons. Whether each of these pathways controls a distinct developmental process remains unknown. Here we describe a novel knock-in mouse model expressing a chimeric TrkA/TrkC (TrkAC) receptor from TrkA locus. In these mice, prospective nociceptors survived, segregated into appropriate peptidergic and nonpeptidergic subsets, projected normally to distinct laminae of the dorsal spinal cord, but displayed aberrant peripheral target innervation. This study provides the first in vivo evidence that intracellular parts of different Trk receptors are interchangeable to promote survival and maturation of nociceptors and shows that these developmental processes can be uncoupled from peripheral target innervation. Moreover, adult homozygous TrkAC knock-in mice displayed severe deficits in acute and tissue injury-induced pain, representing the first viable adult Trk mouse mutant with a pain phenotype.

神经营养因子（Neurotrophins）及其受体通过激活外周神经元内的多条信号通路，调控细胞存活、基因表达与轴突生长等多种细胞进程。目前学界尚不明确这些通路中的每一条是否均调控特定的发育过程。本研究报道了一种新型敲入（knock-in）小鼠模型，该模型可从TrkA基因座（locus）表达嵌合型TrkA/TrkC（TrkAC）受体。在该模型小鼠中，前体伤害性感受器（nociceptors）可正常存活，分化为肽能与非肽能的正常亚群，并能正常投射至脊髓背角（dorsal spinal cord）的不同板层，但出现了异常的外周靶组织神经支配。本研究首次提供了体内（in vivo）证据，证明不同Trk受体的胞内结构域可互换，以促进伤害性感受器的存活与成熟，同时表明这些发育过程可与外周靶组织神经支配解偶联。此外，成年纯合子（homozygous）TrkAC敲入小鼠表现出严重的急性痛与组织损伤诱导性痛觉缺陷，这是首个可存活的成年Trk家族小鼠突变体，且具有痛表型（phenotype）。