The wiring of the nervous system arises from extensive directional migration of neuronal cell bodies and growth of processes that, somehow, end up forming functional circuits. Thus far, this feat of biological engineering appears to rely on sequences of pathfinding decisions upon local cues, each with little relationship to the anatomical and physiological outcome. Here, we uncover a straightforward cellular mechanism for circuit building whereby a neuronal type directs the development of its future partners. We show that visceral afferents of the head (that innervate taste buds) provide a scaffold for the establishment of visceral efferents (that innervate salivatory glands and blood vessels). In embryological terms, sensory neurons derived from an epibranchial placode-that we show to develop largely independently from the neural crest-guide the directional outgrowth of hindbrain visceral motoneurons and control the formation of neural crest-derived parasympathetic ganglia.uring ontogeny of the nervous system, neuronal cell bodies and processes undergo extensive directional migrations or growths. From both a developmental and evolutionary perspective, it would seem to make sense that the migrating somata and processes of neurons destined to a given circuit would be guided, at least in part, by other partners of the same circuit. However, documented examples of this intuitive way of wiring the brain are few and far between and most identified guidance cues emanate from structures that do not participate in the final connectivity of the system (1, 2). The few exceptions, thus far, include homotypic interactions between pioneers and followers or between peers in axonal tracts (3), the towing of the lateral line-nerve growth cones by their future targets in zebrafish (4), and the guidance of sensory fibers by motor ones in spinal nerves (5). An attractive model to look for such navigational cues among future partners of the same circuit is offered by the visceral neurons of the vertebrate head, which display a high degree of anatomic promiscuity, whereby mixed sensory and motor nerves are formed and motor or sensory nerves traverse sensory or motor ganglia, respectively: this tangled anatomy suggests that some neurons might depend on others for their development or guidance. In this study, we focused on the facial nerve (nVII) (see schematic; Fig. 1). The sensory fibers of nVII emanate from the viscerosensory neurons of the geniculate ganglion. These neurons, primarily concerned with taste, project centrally to the nucleus of the solitary tract (nTS) and peripherally to taste buds through the greater superficial petrosal nerve (GSPN) and the corda tympani (CT). The motor fibers of nVII are of two types: visceromotor and branchiomotor. The visceromotor axons emanate from the salivatory motoneurons of the hindbrain, traverse the geniculate ganglion, and course in the GSPN and CT to synapse on parasympathetic neurons of the sphenopalatine ganglion (Spg) and the submandibular and lingual ganglia (S/Lg), respectively, w...
Actin-myosin II filament-based contractile structures in striated muscle, smooth muscle, and nonmuscle cells contain the actin filament-cross-linking protein ␣-actinin. In striated muscle Z-disks, ␣-actinin interacts with N-terminal domains of titin to provide a structural linkage crucial for the integrity of the sarcomere. We previously discovered a long titin isoform, originally smitin, hereafter sm-titin, in smooth muscle and demonstrated that native sm-titin interacts with C-terminal EF hand region and central rod R2-R3 spectrin-like repeat region sites in ␣-actinin. Reverse transcription-PCR analysis of RNA from human adult smooth muscles and cultured rat smooth muscle cells and Western blot analysis with a domain-specific antibody presented here revealed that sm-titin contains the titin geneencoded Zq domain that may bind to the ␣-actinin R2-R3 central rod domain as well as Z-repeat domains that bind to the EF hand region. We investigated whether the sm-titin Zq domain binds to ␣-actinin R2 and R3 spectrin repeat-like domain loops that lie in proximity with two-fold symmetry on the surface of the central rod. Mutations in ␣-actinin R2 and R3 domain loop residues decreased interaction with expressed sm-titin Zq domain in glutathione S-transferase pull-down and solid phase binding assays. Alanine mutation of a region of the Zq domain with high propensity for ␣-helix formation decreased apparent Zq domain dimer formation and decreased Zq interaction with the ␣-actinin R2-R3 region in surface plasmon resonance assays. We present a model in which two sm-titin Zq domains interact with each other and with the two R2-R3 sites in the ␣-actinin central rod.
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