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International Journal of Molecular... Aug 2021During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final... (Review)
Review
During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues "signals" bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models.
Topics: Animals; Axon Guidance; Axons; Axotomy; Growth Cones; Humans; Nerve Regeneration; Signal Transduction
PubMed: 34361110
DOI: 10.3390/ijms22158344 -
Journal of Molecular Biology Feb 2024UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the... (Review)
Review
UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR and AMPK and relay them to the downstream components of the autophagy machinery. ULK1/2 also play indispensable roles in the selective autophagy pathway, removing damaged mitochondria, invading pathogens, and toxic protein aggregates. Additional functions of ULK1/2 have emerged beyond autophagy, including roles in protein trafficking, RNP granule dynamics, and signaling events impacting innate immunity, axon guidance, cellular homeostasis, and cell fate. Therefore, it is no surprise that alterations in ULK1/2 expression and activity have been linked with pathophysiological processes, including cancer, neurological disorders, and cardiovascular diseases. Growing evidence suggests that ULK1/2 function as biological rheostats, tuning cellular functions to intra and extra-cellular cues. Given their broad physiological relevance, ULK1/2 are candidate targets for small molecule activators or inhibitors that may pave the way for the development of therapeutics for the treatment of diseases in humans.
PubMed: 38311233
DOI: 10.1016/j.jmb.2024.168472 -
Protein & Cell Apr 2023Neurons migrate from their birthplaces to the destinations, and extending axons navigate to their synaptic targets by sensing various extracellular cues in... (Review)
Review
Neurons migrate from their birthplaces to the destinations, and extending axons navigate to their synaptic targets by sensing various extracellular cues in spatiotemporally controlled manners. These evolutionally conserved guidance cues and their receptors regulate multiple aspects of neural development to establish the highly complex nervous system by mediating both short- and long-range cell-cell communications. Neuronal guidance genes (encoding cues, receptors, or downstream signal transducers) are critical not only for development of the nervous system but also for synaptic maintenance, remodeling, and function in the adult brain. One emerging theme is the combinatorial and complementary functions of relatively limited classes of neuronal guidance genes in multiple processes, including neuronal migration, axonal guidance, synaptogenesis, and circuit formation. Importantly, neuronal guidance genes also regulate cell migration and cell-cell communications outside the nervous system. We are just beginning to understand how cells integrate multiple guidance and adhesion signaling inputs to determine overall cellular/subcellular behavior and how aberrant guidance signaling in various cell types contributes to diverse human diseases, ranging from developmental, neuropsychiatric, and neurodegenerative disorders to cancer metastasis. We review classic studies and recent advances in understanding signaling mechanisms of the guidance genes as well as their roles in human diseases. Furthermore, we discuss the remaining challenges and therapeutic potentials of modulating neuronal guidance pathways in neural repair.
Topics: Humans; Axon Guidance; Neurons; Axons; Signal Transduction; Cell Communication
PubMed: 36942388
DOI: 10.1093/procel/pwac030 -
Oral Diseases Nov 2022The COVID-19 pandemic caused by SARS-CoV-2 virus quickly spread globally, infecting over half a billion individuals, and killing over 6 million*. One of the more unusual... (Review)
Review
The COVID-19 pandemic caused by SARS-CoV-2 virus quickly spread globally, infecting over half a billion individuals, and killing over 6 million*. One of the more unusual symptoms was patients' complaints of sudden loss of smell and/or taste, a symptom that has become more apparent as the virus mutated into different variants. Anosmia and ageusia, the loss of smell and taste, respectively, seem to be transient for some individuals, but for others persists even after recovery from the infection. Causes for COVID-19-associated chemosensory loss have undergone several hypotheses. These include non-functional or destroyed olfactory neurons and gustatory receptors or of their supporting cells, disruption of the signaling protein Neuropilin-1, and disruption in the interaction with semaphorins, key molecules in the gustatory and olfactory axon guidance. The current paper will review these hypotheses and chart out potential therapeutic avenues.
Topics: Humans; COVID-19; Pandemics; SARS-CoV-2; Taste Disorders; Olfaction Disorders; Anosmia
PubMed: 35790059
DOI: 10.1111/odi.14300 -
Frontiers in Molecular Neuroscience 2022Ischemic stroke is one of the major causes of neurological morbidity and mortality in the world. Although the management of ischemic stroke has been improved... (Review)
Review
Ischemic stroke is one of the major causes of neurological morbidity and mortality in the world. Although the management of ischemic stroke has been improved significantly, it still imposes a huge burden on the health and property. The integrity of the neurovascular unit (NVU) is closely related with the prognosis of ischemic stroke. Growing evidence has shown that semaphorins, a family of axon guidance cues, play a pivotal role in multiple pathophysiological processes in NVU after ischemia, such as regulating the immune system, angiogenesis, and neuroprotection. Modulating the NVU function semaphorin signaling has a potential to develop a novel therapeutic strategy for ischemic stroke. We, therefore, review recent progresses on the role of semphorin family members in neurons, glial cells and vasculature after ischemic stroke.
PubMed: 35350431
DOI: 10.3389/fnmol.2022.848506 -
Materials Today. Bio Jan 2022Single-neuron actions are the basis of brain function, as clinical sequelae, neuronal dysfunction or failure for most of the central nervous system (CNS) diseases and... (Review)
Review
Single-neuron actions are the basis of brain function, as clinical sequelae, neuronal dysfunction or failure for most of the central nervous system (CNS) diseases and injuries can be identified via tracing single-neurons. The bulk analysis methods tend to miscue critical information by assessing the population-averaged outcomes. However, its primary requisite in neuroscience to analyze single-neurons and to understand dynamic interplay of neurons and their environment. Microfluidic systems enable precise control over nano-to femto-liter volumes via adjusting device geometry, surface characteristics, and flow-dynamics, thus facilitating a well-defined micro-environment with spatio-temporal control for single-neuron analysis. The microfluidic platform not only offers a comprehensive landscape to study brain cell diversity at the level of transcriptome, genome, and/or epigenome of individual cells but also has a substantial role in deciphering complex dynamics of brain development and brain-related disorders. In this review, we highlight recent advances of microfluidic devices for single-neuron analysis, i.e., single-neuron trapping, single-neuron dynamics, single-neuron proteomics, single-neuron transcriptomics, drug delivery at the single-neuron level, single axon guidance, and single-neuron differentiation. Moreover, we also emphasize limitations and future challenges of single-neuron analysis by focusing on key performances of throughput and multiparametric activity analysis on microfluidic platforms.
PubMed: 35243297
DOI: 10.1016/j.mtbio.2022.100222 -
Experimental & Molecular Medicine Apr 2022The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin... (Review)
Review
The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.
Topics: Agouti-Related Protein; Humans; Hypothalamus; Melanocortins; Obesity; Peptides; Pro-Opiomelanocortin
PubMed: 35474338
DOI: 10.1038/s12276-021-00625-8 -
Wiley Interdisciplinary Reviews. RNA Jul 2020Alternative pre-mRNA splicing generates multiple mRNA isoforms of different structures and functions from a single gene. While the prevalence of alternative splicing... (Review)
Review
Alternative pre-mRNA splicing generates multiple mRNA isoforms of different structures and functions from a single gene. While the prevalence of alternative splicing control is widely recognized, and the underlying regulatory mechanisms have long been studied, the physiological relevance and biological necessity for alternative splicing are only slowly being revealed. Significant inroads have been made in the brain, where alternative splicing regulation is particularly pervasive and conserved. Various aspects of brain development and function (from neurogenesis, neuronal migration, synaptogenesis, to the homeostasis of neuronal activity) involve alternative splicing regulation. Recent studies have begun to interrogate the possible role of alternative splicing in axon formation, a neuron-exclusive morphological and functional characteristic. We discuss how alternative splicing plays an instructive role in each step of axon formation. Converging genetic, molecular, and cellular evidence from studies of multiple alternative splicing regulators in different systems shows that a biological process as complicated and unique as axon formation requires highly coordinated and specific alternative splicing events. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Development.
Topics: Alternative Splicing; Animals; Axons; Humans; RNA, Messenger
PubMed: 31922356
DOI: 10.1002/wrna.1585 -
Science Advances Oct 2020Homeoproteins were originally identified for embryonic cell-autonomous transcription activity, but they also have non-cell-autonomous activity owing to transfer between... (Review)
Review
Homeoproteins were originally identified for embryonic cell-autonomous transcription activity, but they also have non-cell-autonomous activity owing to transfer between cells. This Review discusses transfer mechanisms and focuses on some established functions, such as neurodevelopmental regulation of axon guidance, and postnatal critical periods of brain plasticity that affect sensory processing and cognition. Homeoproteins are present across all eukaryotes, and intercellular transfer occurs in plants and animals. Proposed functions have evolutionary relevance, such as morphogenetic activity and sexual exchange during the mating of unicellular eukaryotes, while others have physiopathological relevance, such as regulation of mood and cognition by influencing brain compartmentalization, connectivity, and plasticity. There are more than 250 known homeoproteins with conserved transfer domains, suggesting that this is a common mode of signal transduction but with many undiscovered functions.
PubMed: 33115744
DOI: 10.1126/sciadv.abc6374 -
American Journal of Neurodegenerative... 2021The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to... (Review)
Review
The prevalence of neurodegenerative diseases is accelerating in rapidly aging global population. Novel and effective diagnostic and therapeutic methods are required to tackle the global issue of neurodegeneration in the future. A better understanding of the potential molecular mechanism causing neurodegeneration can shed light on dysfunctional processes in diseased neurons, which can pave the way to design and synthesize novel targets for early diagnosis during the asymptomatic phase of the disease. Abnormal protein aggregation is a hallmark of neurodegenerative diseases which can hamper transportation of cargoes into axons. Recent evidence suggests that disruption of local protein synthesis has been observed in neurodegenerative diseases. Because of their highly asymmetric structure, highly polarized neurons require trafficking of cargoes from the cell body to different subcellular regions to meet the extensive demands of cellular physiology. Localization of mRNAs and subsequent local translation to corresponding proteins in axons is a mechanism which allows neurons to rapidly respond to external stimuli as well as establishing neuronal networks by synthesizing proteins on demand. Axonal protein synthesis is required for axon guidance, synapse formation and plasticity, axon maintenance and regeneration in response to injury. Different types of excitatory and inhibitory neurons in the central and peripheral nervous systems have been shown to localize mRNA. Rising evidence suggests that the repertoire of localizing mRNA in axons can change during aging, indicating a connection between axonal mRNA trafficking and aging diseases such as neurodegeneration. Here, I briefly review the latest findings on the importance of mRNA localization and local translation in neurons and the consequences of their disruption in neurodegenerative diseases. In addition, I discuss recent evidence that dysregulation of mRNA localization and local protein translation can contribute to the formation of neurodegenerative diseases such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. In addition, I discuss recent findings on mRNAs localizing to mitochondria in neurodegeneration.
PubMed: 33815964
DOI: No ID Found