Journal: Developmental neurobiology
During neural tube formation, neural plate cells migrate from the lateral aspects of the dorsal surface towards the midline. Elevation of the lateral regions of the neural plate produces the neural folds which then migrate to the midline where they fuse at their dorsal tips, generating a closed neural tube comprising an apicobasally polarized neuroepithelium. Our previous study identified a novel role for the axon guidance receptor neogenin in Xenopus neural tube formation. We demonstrated that loss of neogenin impeded neural fold apposition and neural tube closure. This study also revealed that neogenin, via its interaction with its ligand, RGMa, promoted cell-cell adhesion between neural plate cells as the neural folds elevated and between neuroepithelial cells within the neural tube. The second neogenin ligand, netrin-1, has been implicated in cell migration and epithelial morphogenesis. Therefore, we hypothesized that netrin-1 may also act as a ligand for neogenin during neurulation. Here we demonstrate that morpholino knockdown of Xenopus netrin-1 results in delayed neural fold apposition and neural tube closure. We further show that netrin-1 functions in the same pathway as neogenin and RGMa during neurulation. However, contrary to the role of neogenin-RGMa interactions, neogenin-netrin-1 interactions are not required for neural fold elevation or adhesion between neuroepithelial cells. Instead, our data suggest that netrin-1 contributes to the migration of the neural folds towards the midline. We conclude that both neogenin ligands work synergistically to ensure neural tube closure. © 2012 Wiley Periodicals, Inc., 2013.
Neurogenesis is the process of neuron generation, which occurs not only during embryonic development but also in restricted niches postnatally. One such region is called the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb (OB). Neurons that are born postnatally migrate through more complex territories and integrate into fully functional circuits. Therefore, differences in the differentiation of embryonic and postnatally born neurons may exist. Dendritogenesis is an important process for the proper formation of future neuronal circuits. Dendritogenesis in embryonic neurons cultured in vitro was shown to depend on the mammalian target of rapamycin (mTOR). Still unknown, however, is whether mTOR could regulate the dendritic arbor morphology of SVZ-derived postnatal OB neurons under physiological conditions in vivo. The present study used in vitro cultured and differentiated SVZ-derived neural progenitors and found that both mTOR complex 1 and mTOR complex 2 are required for the dendritogenesis of SVZ-derived neurons. Furthermore, using a combination of in vivo electroporation of neural stem cells in the SVZ and genetic and pharmacological inhibition of mTOR, we found that mTOR is crucial for the growth of basal and apical dendrites in postnatally born OB neurons under physiological conditions and contributes to the stabilization of their basal dendrites. This article is protected by copyright. All rights reserved.
Cranial nerves innervate head muscles in a well-characterised and highly conserved pattern. Identification of genes responsible for human congenital disorders of these nerves, combined with the analysis of their role in axonal development in animal models has advanced understanding of how neuromuscular connectivity is established. Here we focus on the ocular motor system, as an instructive example of the success of this approach in unravelling the aetiology of human strabismus. The discovery that ocular motility disorders can arise from mutations in transcription factors, including HoxA1, HoxB1, MafB, Phox2A and Sall4, has revealed gene regulatory networks that pattern the brainstem and/or govern the differentiation of cranial motor neurons. Mutations in genes involved in axon growth and guidance disrupt specific stages of the extension and pathfinding of ocular motor nerves, and been implicated in human strabismus. These genes encompass varied classes of molecule, from receptor complexes to dynamic effectors to cytoskeletal components, including Robo3/Rig1, Alpha2-chimaerin, Kif21A, TUBB2 and TUBB3. A current challenge is understanding the protein regulatory networks that link the cell surface to the cytoskeleton and dissecting the co-ordinated signalling cascades and motile responses that underpin axonal navigation. We review recent insights derived from basic and clinical science approaches, to show how, by capitalising on the strengths of each, a more complete picture of the aetiology of human congenital cranial dysinnervation disorders can be achieved. This elucidation of these principles illustrates the success of clinical genetic studies working in tandem with molecular and cellular models to enhance understanding of human disease. This article is protected by copyright. All rights reserved.
Dendrites and spines are the main neuronal structures receiving input from other neurons and glial cells. Dendritic and spine number, size and morphology are some of the crucial factors determining how signals coming from individual synapses are integrated. Much remains to be understood about the characteristics of neuronal dendrites and dendritic spines in autism and related disorders. Though there have been many studies conducted using autism mouse models, few have been carried out using postmortem human tissue from patients. Available animal models of autism include those generated through genetic modifications and those non-genetic models of the disease. Here, we review how dendrite and spine morphology and number is affected in autism and related neurodevelopmental diseases, both in human, and genetic and non-genetic animal models of autism. Overall, data obtained from human and animal models point to a generalized reduction in the size and number, as well as an alteration of the morphology of dendrites; and an increase in spine densities with immature morphology, indicating a general spine immaturity state in autism. Additional human studies on dendrite and spine number and morphology in postmortem tissue are needed to understand the properties of these structures in the cerebral cortex of patients with autism. This article is protected by copyright. All rights reserved.
Electrical coupling in circuits can produce non-intuitive circuit dynamics, as seen in both experimental work from the crustacean stomatogastric ganglion and in computational models inspired by the connectivity in this preparation. Ambiguities in interpreting the results of electrophysiological recordings can arise if sets of pre- or postsynaptic neurons are electrically coupled, or if the electrical coupling exhibits some specificity (e.g. rectifying, or voltage-dependent). Even in small circuits, electrical coupling can produce parallel pathways that can allow information to travel by monosynaptic and/or polysynaptic pathways. Consequently, similar changes in circuit dynamics can arise from entirely different underlying mechanisms. When neurons are coupled both chemically and electrically, modifying the relative strengths of the two interactions provides a mechanism for flexibility in circuit outputs. This, together with neuromodulation of gap junctions and coupled neurons is important both in developing and adult circuits. This article is protected by copyright. All rights reserved.
Oxytocin (OXT) signaling through the OXT receptor plays a significant role in a variety of physiological processes throughout the lifespan. OXT’s effects depend on the tissue distribution of the receptor. This tissue specificity is dynamic and changes across development, and also varies with sex, experience, and species. The purpose of this review is to highlight these themes with examples from several life stages and several species. Important knowledge gaps will also be emphasized. Understanding the effective sites of action for OXT via its receptor will help refine hypotheses about the roles of this important neuropeptide in the experience-dependent development and expression of species-typical social behavior. © 2016 Wiley Periodicals, Inc. Develop Neurobiol, 2016.
Microglia as immune cells of the central nervous system (CNS) play significant roles not only in pathology but also in physiology, such as shaping of the CNS during development and its proper maintenance in maturity. Emerging research is showing a close association between microglia and neurovasculature that is critical for brain energy supply. In this review, we summarize the current literature on microglial interaction with the vascular system in the normal and diseased brain. First, we highlight data that indicate interesting potential involvement of microglia in developmental angiogenesis. Then we discuss the evidence for microglial participation with the vasculature in neuropathologies from brain tumors to acute injuries such as ischemic stroke to chronic neurodegenerative conditions. We conclude by suggesting future areas of research to advance the field in light of current technical progress and outstanding questions. This article is protected by copyright. All rights reserved.
RNA localization to neuronal dendrites and axons is increasingly recognized as a significant and widespread mechanism of gene expression control in neurons. High-throughput RNA sequencing is rapidly expanding the universe of known localized mRNAs. Although there are inherent difficulties in preparing sequencing libraries from dendrites and axons in the context of intact brain, genetic labeling strategies have paved the way for improved studies of this type. As the list of localized mRNAs grows, there is increasing need for functional validation of localized transcripts - that is, do particular localized transcripts serve demonstrable physiologic functions in axons or dendrites? Finally, specific details about what localized mRNAs do once they reach distal processes have long been elusive. Recent work using single-molecule imaging and other techniques is starting to fill in the picture of how transcripts navigate the localized environment and undergo activity-dependent translational de-repression. This article is protected by copyright. All rights reserved.
Microglia are the innate immune cells of the central nervous system and are also important participants in normal development and synaptic plasticity. Here we demonstrate that the microglia of the mouse cerebellum represent a unique population compared to cortical microglia. Microglia are more sparsely distributed within the cerebellum and have a markedly less ramified morphology compared to their cortical counterparts. Using time-lapse in vivo imaging, we found that these differences in distribution and morphology ultimately lead to decreased parenchymal surveillance by cerebellar microglia. We also observed a novel form of somal motility in cerebellar microglia in vivo, which has not been described in cortical populations. We captured microglial interactions with Purkinje neurons in vivo. Cerebellar microglia interact dynamically with both the dendritic arbors and somas of Purkinje neurons. These findings suggest that cerebellar microglia are physiologically distinct from cortical populations and that these differences may ultimately alter how they could contribute to plasticity and disease processes in the cerebellum. This article is protected by copyright. All rights reserved.
Investigations on the role of microglia in the brain have traditionally been focused on their contributions to disease states. However, recent observations have now convincingly shown that microglia in the healthy brain are not passive bystanders, but instead play a critical role in both central nervous system development and homeostasis of synaptic circuits in the adult. Here, we review the various mechanisms by which microglia impact neuronal communication in the healthy adult brain, both by sensing nearby synaptic responses and by actively modulating neuronal function. This article is protected by copyright. All rights reserved.