Harnessing PTEN’s Growth Potential in Neuronal Development and Disease

PTEN is a powerful regulator of neuronal growth. It globally suppresses axon extension and branching during both nervous system development and regeneration, by antagonizing growth-promoting PI3K/PI(3,4,5)P3 signaling. We recently identified that the transmembrane protein PRG2/LPPR3 functions as a modulator of PTEN function during axon morphogenesis. Our work demonstrates that through inhibition of PTEN activity, PRG2 stabilizes membrane PI(3,4,5)P3. In turn, PRG2 deficiency attenuates the formation of branches in a PTEN-dependent manner, albeit without affecting the overall growth capacity of extending axons. Thus, PRG2 is poised to temporally and locally relieve growth suppression mediated by PTEN in neurons and, in effect, to redirect growth specifically to axonal branches. In this commentary, we discuss potential implications and unresolved questions regarding the regulation of axonal PTEN in neurons. Given their widespread implication during neuronal development and regeneration, identification of mechanisms that confer spatiotemporal control of PTEN may unveil new approaches to reprogram PI3K signaling in neurodevelopmental disorders and regeneration research.

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Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22115524 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5524

Author(s):

Kazuma Sakamoto ◽

Tomoya Ozaki ◽

Yuji Suzuki ◽

Kenji Kadomatsu

Keyword(s):

Heparan Sulfate ◽

Network Formation ◽

Synapse Formation ◽

Axon Regeneration ◽

Transmembrane Protein ◽

Inhibitory Synapses ◽

Dependent Manner ◽

Axon Terminals ◽

Axon Extension ◽

Receptor Tyrosine Phosphatases

Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.

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UNC-16/JIP3 negatively regulates actin dynamics dependent on DLK-1 and microtubule dynamics independent of DLK-1 in regenerating neurons

10.1101/484683 ◽

2018 ◽

Author(s):

Sucheta S. Kulkarni ◽

Vidur Sabharwal ◽

Seema Sheoran ◽

Atrayee Basu ◽

Kunihiro Matsumoto ◽

...

Keyword(s):

Axonal Regeneration ◽

Microtubule Dynamics ◽

Growth Potential ◽

Actin Dynamics ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

C Elegans ◽

Growth Promoting ◽

Temporal And Spatial

AbstractNeuronal regeneration after injury depends on the intrinsic growth potential of neurons. UNC-16, a C. elegans JIP3 homologue, inhibits axonal regeneration by regulating regrowth initiation and rate of regrowth. UNC-16/JIP3 inhibits the regeneration promoting activity of DLK-1 long but acts additively to and independently of inhibitory DLK-1 short isoform. UNC-16/JIP3 promotes DLK-1 punctate localization in a concentration dependent manner limiting DLK-1 long availability at the cut site minutes after injury. UNC-16 negatively regulates actin dynamics dependent on DLK-1 and microtubule dynamics independent of DLK-1. The faster regeneration seen in unc-16 does not lead to functional recovery. We propose a model where UNC-16/JIP3 plays its inhibitory role through tight temporal and spatial control of DLK-1 function. The dual inhibitory control by both UNC-16 and DLK-1 short calibrate the intrinsic growth promoting function of DLK-1 long in vivo.

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Repression of an activity-dependent autocrine insulin signal is required for sensory neuron development in C. elegans

10.1101/481010 ◽

2018 ◽

Author(s):

Lauren Bayer Horowitz ◽

Julia P. Brandt ◽

Niels Ringstad

Keyword(s):

Nervous System ◽

System Development ◽

Nervous System Development ◽

P38 Map Kinase ◽

Dependent Manner ◽

Neuron Development ◽

C Elegans ◽

Chemosensory Neuron ◽

Insulin Receptor Signaling ◽

Activity Dependent

AbstractNervous system development is instructed both by genetic programs and activity-dependent refinement of gene expression and connectivity. How these mechanisms are integrated remains poorly understood. Here, we report that the regulated release of insulin-like peptides (ILPs) during development of the C. elegans nervous system accomplishes such an integration. We find that the p38 MAP kinase PMK-3, which is required for the differentiation of chemosensory BAG neurons, functions by limiting expression of an autocrine ILP signal that represses a chemosensory-neuron fate. ILPs are released from BAGs in an activity-dependent manner during embryonic development, and regulate neurodifferentiation through a non-canonical insulin receptor signaling pathway. The differentiation of a specialized neuron-type is, therefore, coordinately regulated by a genetic program that controls ILP expression and by neural activity, which regulates ILP release. Autocrine signals of this kind may have general and conserved functions as integrators of deterministic genetic programs with activity-dependent mechanisms during neurodevelopment.

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Postnatal testosterone may be an important mediator of the association between prematurity and male neurodevelopmental disorders: a hypothesis

International Journal of Adolescent Medicine and Health ◽

10.1515/ijamh-2015-0047 ◽

2017 ◽

Vol 29 (2) ◽

Cited By ~ 4

Author(s):

Timothy R. Rice

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodevelopmental Disorders ◽

System Development ◽

Explanatory Power ◽

Autism Spectrum ◽

Nervous System Development ◽

Special Focus ◽

Important Mediator ◽

Androgen Exposure

Abstract Children born premature are at risk for neurodevelopmental disorders, including autism and schizophrenia. This piece advances the hypothesis that altered androgen exposure observed in premature infants is an important mediator of the neurodevelopmental risk in males associated with prematurity. Specifically, the alterations of normative physiologic postnatal activations of the hypothalamic-pituitary-gonadal axis that occur in preterm males are hypothesized to contribute to the risk of neuropsychiatric pathology of prematurity through altered androgen-mediated organizational effects on the developing brain. The physiology of testosterone and male central nervous system development in full-term births is reviewed and compared to the developmental processes of prematurity. The effects of the altered testosterone physiology observed within prematurity outside of the central nervous system are reviewed as a segue into a discussion of the effects within the nervous system, with a special focus on autism spectrum disorders and attention deficit hyperactivity disorder. The explanatory power of this model is reviewed as a supplement to the preexisting models of prematurity and neurodevelopmental risk, including infection and other perinatal central nervous system insults. The emphasis is placed on altered androgen exposure as serving as just one among many mediators of neurodevelopmental risk that may be of interest for further research and evidence-based investigation. Implications for diagnosis, management and preventative treatments conclude the piece.

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Genes required for axon pathfinding and extension in the C. elegans nerve ring

Development ◽

10.1242/dev.126.16.3679 ◽

1999 ◽

Vol 126 (16) ◽

pp. 3679-3692 ◽

Cited By ~ 4

Author(s):

J.A. Zallen ◽

S.A. Kirch ◽

C.I. Bargmann

Keyword(s):

Axon Guidance ◽

Fluorescent Protein ◽

System Development ◽

Axon Growth ◽

Ring Structure ◽

Nervous System Development ◽

Nerve Ring ◽

Eph Receptor ◽

Axon Extension ◽

Growth Guidance

Over half of the neurons in Caenorhabditis elegans send axons to the nerve ring, a large neuropil in the head of the animal. Genetic screens in animals that express the green fluorescent protein in a subset of sensory neurons identified eight new sax genes that affect the morphology of nerve ring axons. sax-3/robo mutations disrupt axon guidance in the nerve ring, while sax-5, sax-9 and unc-44 disrupt both axon guidance and axon extension. Axon extension and guidance proceed normally in sax-1, sax-2, sax-6, sax-7 and sax-8 mutants, but these animals exhibit later defects in the maintenance of nerve ring structure. The functions of existing guidance genes in nerve ring development were also examined, revealing that SAX-3/Robo acts in parallel to the VAB-1/Eph receptor and the UNC-6/netrin, UNC-40/DCC guidance systems for ventral guidance of axons in the amphid commissure, a major route of axon entry into the nerve ring. In addition, SAX-3/Robo and the VAB-1/Eph receptor both function to prevent aberrant axon crossing at the ventral midline. Together, these genes define pathways required for axon growth, guidance and maintenance during nervous system development.

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Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2

Molecular Biology of the Cell ◽

10.1091/mbc.e05-07-0700 ◽

2006 ◽

Vol 17 (3) ◽

pp. 1273-1285 ◽

Cited By ~ 76

Author(s):

Takashi Nishimura ◽

Tomoya Yamaguchi ◽

Akinori Tokunaga ◽

Akitoshi Hara ◽

Tomonari Hamaguchi ◽

...

Keyword(s):

Dendritic Spine ◽

Hippocampal Neurons ◽

Neuronal Development ◽

System Development ◽

Direct Interaction ◽

Nervous System Development ◽

Nucleotide Exchange ◽

Spine Development

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.

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Retinoic acid induces changes in electrical properties of adult neurons in a dose- and isomer-dependent manner

Journal of Neurophysiology ◽

10.1152/jn.00434.2013 ◽

2014 ◽

Vol 111 (6) ◽

pp. 1318-1330 ◽

Cited By ~ 10

Author(s):

Nicholas D. Vesprini ◽

Gaynor E. Spencer

Keyword(s):

Nervous System ◽

Retinoic Acid ◽

Electrical Properties ◽

Electrical Activity ◽

Neuronal Development ◽

Lymnaea Stagnalis ◽

Critical Role ◽

Nervous System Development ◽

Neuronal Firing ◽

Dependent Manner

The electrical activity of neurons is known to play a role in neuronal development, as well as repair of adult nervous tissue. For example, the extension of neurites and motility of growth cones can be modulated by changes in the electrical firing of neurons. The vitamin A metabolite retinoic acid also plays a critical role during nervous system development and is also known to elicit regenerative responses, namely the induction, enhancement, and directionality of neurite outgrowth. However, no studies have previously reported the ability of retinoic acid to modify the electrical activity of neurons. In this study, we determined whether retinoic acid might exert effects on the nervous system by altering the electrical properties of neurons. Using cultured adult neurons from Lymnaea stagnalis, we showed that acute application of retinoic acid can rapidly elicit changes in neuronal firing properties. Retinoic acid caused the presence of atypical firing behavior such as rhythmic bursting and altered the shape of action potentials, causing increases in half-amplitude duration and decay time. Retinoic acid also caused cell silencing, whereby neuronal activity was halted within an hour. These effects of retinoic acid were shown to be both dose and isomer dependent. We then showed that the effects of retinoic acid on cell firing (but not silencing) were significantly reduced in the presence of an retinoid X receptor pan-antagonist HX531. This study suggests that some of the effects of retinoic acid during neuronal development or regeneration might possibly occur as a result of changes in electrical activity of neurons.

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Unraveling Axon Guidance during Axotomy and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22158344 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8344

Author(s):

Miguel E. Domínguez-Romero ◽

Paula G. Slater

Keyword(s):

Nervous System ◽

Growth Cone ◽

Neuronal Development ◽

System Development ◽

Nervous System Development ◽

Signaling Cascades ◽

Final Destination ◽

Guidance Cues ◽

The Central Nervous System ◽

Do So

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.

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Elongation of Caudalized Human Organoids Mimics Neural Tube Development

10.1101/2020.03.05.979732 ◽

2020 ◽

Cited By ~ 2

Author(s):

ARG Libby ◽

DA Joy ◽

NH Elder ◽

EA Bulger ◽

MZ Krakora ◽

...

Keyword(s):

Gene Expression ◽

Neural Tube ◽

System Development ◽

Expression Patterns ◽

Nervous System Development ◽

Paraxial Mesoderm ◽

Dependent Manner ◽

Axial Elongation ◽

Temporal Gene Expression ◽

Neural Tube Development

AbstractAxial elongation of the neural tube is critical during mammalian embryogenesis to establish the anterior-posterior body axis1, but this process is difficult to interrogate directly because it occurs post-implantation2,3. Here we report an organoid model of neural tube extension by caudalized human pluripotent stem cell (hPSC) aggregates that recapitulates the morphologic and temporal gene expression patterns of neural tube development. Axially extending organoids consisting largely of longitudinally elongated neuroepithelial compartments also contained TBXT(+)SOX2(+) neuromesodermal progenitors, PAX6(+)nestin(+) neural progenitor populations, and MEOX1(+) paraxial mesoderm populations. Wnt agonism stimulated singular axial extensions in a dose-dependent manner, and elongated organoids displayed regionalized rostral-caudal HOX gene expression, with spatially distinct hindbrain (HOXB1) expression from brachial (HOXC6) and thoracic (HOXB9) regions. CRISPR-interference-mediated silencing of the TBXT, a downstream Wnt target, increased neuroepithelial compartmentalization and resulted in multiple extensions per aggregate. Further, knock-down of BMP inhibitors, Noggin and Chordin, induced elongation phenotypes that mimicked murine knockout models. These results indicate the potent morphogenic capacity of caudalized hPSC organoids to undergo axial elongation in a manner that can be used to dissect the cellular organization and patterning decisions that dictate early nervous system development in humans.

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Dynamics of neurotransmitter and extracellular vesicle-derived microRNA landscapes during heroin and methamphetamine withdrawal

10.1101/2021.04.19.21255653 ◽

2021 ◽

Author(s):

Juehua Yu ◽

Fengrong Chen ◽

Yu Xu ◽

Kai Shi ◽

Zunyue Zhang ◽

...

Keyword(s):

Neuronal Development ◽

System Development ◽

Extracellular Vesicle ◽

Neuronal Model ◽

Nervous System Development ◽

Bioinformatics Analyses ◽

Cross Sectional ◽

And Function ◽

Substance Withdrawal

AbstractCirculating miRNAs in small vesicles known as exosomes within blood have been emerging as a new research hotspot in the field of psychiatric disorders. The aim of this work was to characterize the changes in exosomal microRNA profiles, both short-term and long-term, during substance withdrawal using a cross-sectional study design. Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal microRNAs were identified as being associated with withdrawal stage and key neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are associated with developmental and intellectual abnormalities. Notably, a set of dysregulated microRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting patients with substance use disorders. Furthermore, hsa-miR-744a-5p was positively correlated with serotonin, and its important role in maintaining neuronal development and function was revealed using an in vitro human induced pluripotent stem cells derived neuronal model. Taken together, these data suggest that the microRNA content of circulating exosomes represent a biomolecular “fingerprint” of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal microRNAs contribute to central nervous system development and function.

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