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PLoS Biology Nov 2022The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during...
The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon development have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS) by experiments using mouse and chick embryos. Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here, we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.
Topics: Chick Embryo; Animals; Mice; Axons; Cerebellum; Spinal Cord; Neurons; Nerve Tissue Proteins; Protein Precursors
PubMed: 36395107
DOI: 10.1371/journal.pbio.3001853 -
Brain and Behavior Sep 2023The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo... (Review)
Review
BACKGROUND
The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo type mechanosensitive ion channel component 1 (Piezo1), a protein found in metazoans, is highly expressed in the brain and involved in sensing changes of the mechanical microenvironment. Numerous studies have shown that Piezo1-mediated mechanotransduction is closely related to glial cell activation and neuronal function. However, the precise role of Piezo1 in the brain requires further elucidation.
OBJECTIVE
This review first discusses the roles of Piezo1-mediated mechanotransduction in regulating the functions of a variety of brain cells, and then briefly assesses the impact of Piezo1-mediated mechanotransduction on the progression of brain dysfunctional disorders.
CONCLUSIONS
Mechanical signaling contributes significantly to brain function. Piezo1-mediated mechanotransduction regulates processes such as neuronal differentiation, cell migration, axon guidance, neural regeneration, and oligodendrocyte axon myelination. Additionally, Piezo1-mediated mechanotransduction plays significant roles in normal aging and brain injury, as well as the development of various brain diseases, including demyelinating diseases, Alzheimer's disease, and brain tumors. Investigating the pathophysiological mechanisms through which Piezo1-mediated mechanotransduction affects brain function will give us a novel entry point for the diagnosis and treatment of numerous brain diseases.
Topics: Humans; Axons; Brain; Brain Neoplasms; Mechanotransduction, Cellular; Neurons; Tumor Microenvironment
PubMed: 37366640
DOI: 10.1002/brb3.3136 -
International Journal of Molecular... May 2020Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function... (Review)
Review
Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function of the brain, and thus the behavior. As the axons travel in the brain to find their target, they encounter various axon guidance cues, which interact with the receptors on the tip of the growth cone to permit growth along different signaling pathways. Although many scientists have performed numerous studies on axon guidance signaling pathways, we still have an incomplete understanding of the axon guidance system. Lately, studies on axon guidance have shifted from studying the signal transduction pathways to studying other molecular features of axon guidance, such as the gene expression. These new studies present evidence for different molecular features that broaden our understanding of axon guidance. Hence, in this review we will introduce recent studies that illustrate different molecular features of axon guidance. In particular, we will review literature that demonstrates how axon guidance cues and receptors regulate local translation of axonal genes and how the expression of guidance cues and receptors are regulated both transcriptionally and post-transcriptionally. Moreover, we will highlight the pathological relevance of axon guidance molecules to specific diseases.
Topics: Animals; Axon Guidance; Axons; Gene Expression Regulation; Humans; Protein Biosynthesis; RNA-Binding Proteins; Signal Transduction
PubMed: 32443632
DOI: 10.3390/ijms21103566 -
STAR Protocols Dec 2021Axons form the long-range connections of biological neuronal networks, which are built through the developmental process of axon guidance. Here, we describe a protocol...
Axons form the long-range connections of biological neuronal networks, which are built through the developmental process of axon guidance. Here, we describe a protocol to precisely and non-invasively control axonal growth trajectories in live zebrafish embryos using focal light activation of a photoactivatable Rac1. We outline techniques for photostimulation, time-lapse imaging, and immunohistochemistry. These approaches enable engineering of long-range axonal circuitry or repair of defective circuits in living zebrafish, despite a milieu of competing endogenous signals and repulsive barriers. For complete details on the use and execution of this protocol, please refer to Harris et al. (2020).
Topics: Animals; Axon Guidance; Embryo, Nonmammalian; Female; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Optogenetics; Time-Lapse Imaging; Zebrafish
PubMed: 34841275
DOI: 10.1016/j.xpro.2021.100947 -
Nature Communications Oct 2023Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and...
Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.
Topics: Humans; Animals; Mice; Glioblastoma; Enhancer Elements, Genetic; Chromatin; Transcription Factors; Gene Expression
PubMed: 37833281
DOI: 10.1038/s41467-023-41919-x -
Frontiers in Cell and Developmental... 2022The development of the nervous system is a time-ordered and multi-stepped process that includes neurogenesis and neuronal specification, axonal navigation, and circuits... (Review)
Review
The development of the nervous system is a time-ordered and multi-stepped process that includes neurogenesis and neuronal specification, axonal navigation, and circuits assembly. During axonal navigation, the growth cone, a dynamic structure located at the tip of the axon, senses environmental signals that guide axons towards their final targets. The expression of a specific repertoire of receptors on the cell surface of the growth cone together with the activation of a set of intracellular transducing molecules, outlines the response of each axon to specific guidance cues. This collection of axon guidance molecules is defined by the transcriptome of the cell which, in turn, depends on transcriptional and epigenetic regulators that modify the structure and DNA accessibility to determine what genes will be expressed to elicit specific axonal behaviors. Studies focused on understanding how axons navigate intermediate targets, such as the floor plate of vertebrates or the mammalian optic chiasm, have largely contributed to our knowledge of how neurons wire together during development. In fact, investigations on axon navigation at these midline structures led to the identification of many of the currently known families of proteins that act as guidance cues and their corresponding receptors. Although the transcription factors and the regulatory mechanisms that control the expression of these molecules are not well understood, important advances have been made in recent years in this regard. Here we provide an updated overview on the current knowledge about the transcriptional control of axon guidance and the selection of trajectories at midline structures.
PubMed: 35265625
DOI: 10.3389/fcell.2022.840005 -
Fly Dec 2022Receptor proteins of the Roundabout (Robo) family regulate axon guidance decisions during nervous system development. Among the three family genes ( and displays a...
Receptor proteins of the Roundabout (Robo) family regulate axon guidance decisions during nervous system development. Among the three family genes ( and displays a dynamic expression pattern and regulates multiple axon guidance outcomes, including preventing midline crossing in some axons, promoting midline crossing in others, forming lateral longitudinal axon pathways, and regulating motor axon guidance. The identity and location of enhancer elements regulating complex and dynamic expression pattern in different neural cell types are unknown. Here, we characterize a set of 17 transgenic lines expressing GAL4 under the control of DNA sequences derived from noncoding regions in and around , to identify enhancers controlling specific aspects of expression in the embryonic ventral nerve cord. We identify individual fragments that confer expression in specific cell types where is known to function, including early pioneer neurons, midline glia and lateral longitudinal neurons. Our results indicate that s dynamic expression pattern is specified by a combination of enhancer elements that are active in different subsets of cells. We show that expression in lateral longitudinal axons represents two genetically separable subsets of neurons, and compare their axon projections with each other and with Fasciclin II (FasII), a commonly used marker of longitudinal axon pathways. In addition, we provide a general description of each fragment's expression in embryonic tissues outside of the nervous system, to serve as a resource for other researchers interested in expression and its functional roles outside the central nervous system.
Topics: Animals; Axons; Drosophila; Drosophila Proteins; Gene Expression Regulation, Developmental; Nerve Tissue Proteins; Receptors, Immunologic
PubMed: 36217698
DOI: 10.1080/19336934.2022.2126259 -
Molecules and Cells Aug 2021Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although... (Review)
Review
Decoding the molecular mechanisms underlying axon guidance is key to precise understanding of how complex neural circuits form during neural development. Although substantial progress has been made over the last three decades in identifying numerous axon guidance molecules and their functional roles, little is known about how these guidance molecules collaborate to steer growth cones to their correct targets. Recent studies in point to the importance of the combinatorial action of guidance molecules, and further show that selective fasciculation and defasciculation at specific choice points serve as a fundamental strategy for motor axon guidance. Here, I discuss how attractive and repulsive guidance cues cooperate to ensure the recognition of specific choice points that are inextricably linked to selective fasciculation and defasciculation, and correct pathfinding decision-making.
Topics: Animals; Axon Fasciculation; Axon Guidance; Drosophila melanogaster; Motor Neurons; Muscles; Neuromuscular Junction
PubMed: 34385406
DOI: 10.14348/molcells.2021.0129 -
Annual Review of Vision Science Sep 2021Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which... (Review)
Review
Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: () defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or () axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.
Topics: Axons; Cranial Nerve Diseases; Eye Movements; Humans; Motor Neurons; Strabismus
PubMed: 34081534
DOI: 10.1146/annurev-vision-093019-114307 -
International Journal of Molecular... Jun 2023Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival,... (Review)
Review
Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics.
Topics: Fibroblast Growth Factors; Receptors, Fibroblast Growth Factor; Axon Guidance; Signal Transduction; Axons
PubMed: 37373438
DOI: 10.3390/ijms241210292