Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
Both spatial and temporal cues determine the fate of immature neurons. A major challenge at the interface of developmental and systems neuroscience is to relate this spatiotemporal trajectory of maturation to circuit‐level functional organization. This study examined the development of two extraocular motor nuclei (nIII and nIV), structures in which a motoneuron's identity, or choice of muscle partner, defines its behavioral role. We used retro‐orbital dye fills, in combination with fluorescent markers for motoneuron location and birthdate, to probe spatial and temporal organization of the oculomotor (nIII) and trochlear (nIV) nuclei in the larval zebrafish. We describe a dorsoventral organization of the four nIII motoneuron pools, in which inferior and medial rectus motoneurons occupy dorsal nIII, while inferior oblique and superior rectus motoneurons occupy distinct divisions of ventral nIII. Dorsal nIII motoneurons are, moreover, born before motoneurons of ventral nIII and nIV. The order of neurogenesis can therefore account for the dorsoventral organization of nIII and may play a primary role in determining motoneuron identity. We propose that the temporal development of extraocular motoneurons plays a key role in assembling a functional oculomotor circuit. J. Comp. Neurol. 525:65–78, 2017. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.
Neuronal control of muscles associated with the central body axis is an ancient and essential function of the nervous systems of most animal species. Throughout the course of vertebrate evolution, motor circuits dedicated to control of axial muscle have undergone significant changes in their roles within the motor system. In most fish species, axial circuits are critical for coordinating muscle activation sequences essential for locomotion and play important roles in postural correction. In tetrapods, axial circuits have evolved unique functions essential to terrestrial life, including maintaining spinal alignment and breathing. Despite the diverse roles of axial neural circuits in motor behaviors, the genetic programs underlying their assembly are poorly understood. In this review, we describe recent studies that have shed light on the development of axial motor circuits and compare and contrast the strategies used to wire these neural networks in aquatic and terrestrial vertebrate species.
Plexins (Plxns) are semaphorin (Sema) receptors that play important signaling roles, particularly in the developing nervous system and vasculature. Sema‐Plxn signaling regulates cellular processes such as cytoskeletal dynamics, proliferation, and differentiation. However, the receptor‐proximal signaling mechanisms driving Sema‐Plxn signal transduction are only partially understood. Plxn tyrosine phosphorylation is thought to play an important role in these signaling events as receptor and nonreceptor tyrosine kinases have been shown to interact with Plxn receptors. The Src family kinase Fyn can induce the tyrosine phosphorylation of PlxnA1 and PlxnA2. However, the Fyn‐dependent phosphorylation sites on these receptors have not been identified. Here, using mass spectrometry‐based approaches, we have identified highly conserved, Fyn‐induced PlexinA (PlxnA) tyrosine phosphorylation sites. Mutation of these sites to phenylalanine results in significantly decreased Fyn‐dependent PlxnA tyrosine phosphorylation. Furthermore, in contrast to wild‐type human PLXNA2 mRNA, mRNA harboring these point mutations cannot rescue eye developmental defects when coinjected with a plxnA2 morpholino in zebrafish embryos. Together these data suggest that Fyn‐dependent phosphorylation at two critical tyrosines is a key feature of vertebrate PlxnA1 and PlxnA2 signal transduction.
Graphical AbstractHighlights d TAG-1 expression during motor neuron development shifts from cell bodies to axons d TAG-1 is required to anchor motor neuron cell bodies in the central nervous system d Motor axons fail to fasciculate and exhibit guidance defects in TAG-1 À/À mice d TAG-1 fulfills its multiple functions independently of one another
Topographic maps are a basic organizational feature of nervous systems, and their construction involves both spatial and temporal cues. A recent study reports a novel mechanism of topographic map formation which relies on the timing of axon initiation.
Semaphorins (Semas) are a family of secreted and transmembrane proteins that play critical roles in the developing nervous system, cardiovasculature, and immune system. Semas signal predominantly through Plexin (Plxn) receptors to regulate cellular processes such as cytoskeletal dynamics, proliferation, and differentiation. We have previously shown that the transmembrane Sema6A and its PlxnA2 receptor are critical in vertebrate eye development, as morpholino‐based knock‐down of these proteins in zebrafish results in decreased early eye field cohesion, smaller eye size, and impaired retinal lamination. Due to the transmembrane nature of Sema6A, reverse signaling can occur and it is thought to contribute to the observed phenotypes. Although several cellular players governing Sema‐Plxn signaling have been identified, the molecular mechanisms that initiate forward and reverse signaling are only partially understood. Therefore, we aimed to investigate the receptor‐proximal events of Sema‐Plxn signaling and we report here two main findings towards a better understanding of the early events of Sema‐Plxn signaling: 1) PlxnA receptor phosphorylation at two tyrosine sites is critical for zebrafish eye development and 2) Sema6A has a functional naturally‐released ectodomain, sSema6A.We used mass spectrometry‐based approaches to identify highly‐conserved, Fyn kinase‐mediated PlxnA tyrosine phosphorylation sites. Mutation of these sites to phenylalanine results in significantly decreased Fyn‐dependent PlxnA tyrosine phosphorylation. Furthermore, in contrast to wildtype human PLXNA2 mRNA, mRNA harboring these point mutations cannot rescue eye developmental defects when co‐injected with a plxnA2 morpholino in zebrafish embryos. Interestingly, while investigating whether or not these sites are phosphorylated upon Sema6A ligand binding, we serendipitously discovered that a functional soluble Sema6A, sSema6A, is spontaneously released from cells expressing the full‐length transmembrane Sema6A. Using zebrafish eye explants, we show that sSema6A promotes early eye field cohesion, a process known to be Sema6A‐dependent. While other soluble Sema ectodomains have been identified in the immune system, we describe here the first soluble ectodomain from a transmembrane Sema that has predominant roles in the nervous system. Together these data suggest that Sema6A may have long‐range effects in addition to its canonical contact‐mediated functions and that Fyn‐dependent phosphorylation is a key feature of vertebrate PlxnA signal transduction. Future work will investigate if the transmembrane and secreted forms of Sema6A can induce Fyn‐mediated PlxnA tyrosine phosphorylation.Support or Funding InformationNational Science Foundation (NSF) IOS grants 1021795 and 1625154; NSF DBI REU grant 1262786;the Vermont Genetics Network through U. S. National Institutes of Health (NIH) Grant 8P20GM103449 from the INBRE program of the NIGMS; and U.S. NIH Grant 5P20RR016435 fromthe COBRE program of the NIGMS.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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