Actin Aggregations Mark the Sites of Neurite Initiation

Zhang, Shuxin; Duan, Lihui; Qian, Hong; Yu, Xiang

doi:10.1007/s12264-016-0012-2

Cited by 18 publications

(28 citation statements)

References 81 publications

(103 reference statements)

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“…To determine whether PIs regulated actin aggregation and neuritogenesis, we first assayed whether PIP 3 , PI(3,4) P 2 or PI(4,5)P 2 co-localized with actin aggregates during early neurite initiation. Cultured hippocampal neurons were fixed 3-6 h after plating, at a developmental stage where they typically had one or two large actin aggregates underneath the plasma membrane, defined as stage 1b in our previous study [23] ( Figure 1F). Neurons were identified by immunostaining for the microtubule-associated protein 2 (MAP2), while filamentous actin (F-actin) was visualized using phalloidin.…”

Section: Pi(34)p 2 Co-localizes With Actin Aggregates During Neuritomentioning

confidence: 99%

“…As compared to the last three stages of neuronal morphogenesis, which have been extensively studied [3][4][5][6][7][8][9][10][11][12][13], relatively little is known regarding the mechanism regulating neuritogenesis -the initial extension of neurites from the spherical soma [14][15][16][17][18][19]. Recent work from a number of laboratories, including our own, demonstrated a critical role of actin aggregation during neuritogenesis [20][21][22][23]. Using a combination of loss-and gain-of-function strategies, as well as pharmacological tools, these studies showed that the redistribution of evenly distributed cortical actin underneath the cell membrane into large actin aggregate(s) was required for neuritogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…Dynamics is key to this process, as actin bundling molecules, such as the Ena/Mena/VASP family of proteins (abbreviated as Ena/VASP), and actin depolymerizing factors, such as actin depolarizing factor (ADF)/Cofilin, have both been shown to be required for mediating local actin aggregation and subsequent neurite initiation from these sites [20][21][22]. In previous work, we subdivided stage 1 into two components, with neurons in stage 1a having evenly distributed cortical actin and those in stage 1b having one or two large actin aggregates directly underneath the plasma membrane [23].…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation

Zhang

Duan

et al. 2017

Cell Res

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Neurite initiation is critical for neuronal morphogenesis and early neural circuit development. Recent studies showed that local actin aggregation underneath the cell membrane determined the site of neurite initiation. An immediately arising question is what signaling mechanism initiated actin aggregation. Here we demonstrate that local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis. In contrast, the related and more extensively studied phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol (3,4,5)-trisphosphate (PIP) molecules did not have such functions. Specifically, we showed that beads coated with PI(3,4)P promoted actin aggregation and neurite initiation, while pharmacological interference with PI(3,4)P synthesis inhibited both processes. PI(3,4)P clustering occurred even when actin aggregation was pharmacologically blocked, demonstrating that PI(3,4)P functioned as the upstream signaling molecule. Two enzymes critical for PI(3,4)P generation, namely, SH2 domain-containing inositol 5-phosphatase and class II phosphoinositide 3-kinase α, were complementarily and non-redundantly required for actin aggregation and neuritogenesis, as well as for subsequent dendritogenesis. Finally, we demonstrate that neural Wiskott-Aldrich syndrome protein and the Arp2/3 complex functioned downstream of PI(3,4)P to mediate neuritogenesis and dendritogenesis. Together, our results identify PI(3,4)P as an important signaling molecule during early development and demonstrate its critical role in regulating actin aggregation and neuritogenesis.

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Section: Pi(34)p 2 Co-localizes With Actin Aggregates During Neuritomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation

Zhang

Duan

et al. 2017

Cell Res

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“…This complex feat is driven by neuronal polarization which causes an initial break in symmetry within an immature neuron, seamlessly followed by the two stages of neuritogenesis: neurite initiation followed by neurite elongation (4, 7, 8). Following neuronal polarization, actin aggregates form the sites of primitive neurites, precursors to the axon and dendrites (4, 9, 10). At these sites, actin rich filopodia and lamellipodia rapidly extend and retract before being stabilized by microtubule invasion.…”

Section: Introductionmentioning

confidence: 99%

14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling

Bennison

Blazejewski

Liu

et al. 2020

Preprint

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30Neurite formation is the earliest stage of neuronal morphogenesis, where primitive 31 dendrites and the primitive axon emerge from a spherical neuron and begin to elongate. Defective 32 neuritogenesis is a contributing pathogenic mechanism behind a variety of neurodevelopmental 33 disorders. Activity-dependent neuroprotective protein (Adnp) is essential to embryonic and 34 postnatal brain development, and mutations in ADNP are among the most frequent underlying 35 autism spectrum disorder (ASD). We found that knockdown of Adnp in vitro and in vivo in mouse 36 layer 2/3 pyramidal neurons leads to increased neurite initiation and defective neurite elongation, 37suggesting that Adnp has distinct roles in each. In vivo analysis revealed that deficits begin at P0 38 and are sustained throughout development, the most notable of which include increased neurite 39 stabilization, disrupted angle of the apical dendrite, increased basal dendrite number, and increased 40 axon length. Because small changes in neuronal morphology can have large-scale effects on 41 neuronal function and connectivity, we performed ex vivo calcium imaging to assess spontaneous 42 function of layer 2/3 pyramidal neurons deficient in Adnp. This revealed that Adnp deficient 43 neurons had a greater spontaneous calcium influx and a higher proportion of cells firing action 44 potentials. Next, we utilized GRAPHIC, a novel synaptic tracing technology, to assess 45 interhemispheric cortical connectivity. We found increased interhemispheric excitatory 46 connectivity between Adnp deficient layer 2/3 pyramidal neurons. Because Adnp is a 47 57Neuritogenesis is a fundamental step of cortical development essential for establishing 58 correct neuronal morphology, connectivity, and function (1, 2). Immature neurons have a spherical 59 morphology that upon maturation develops to extend a single axon and multiple dendrites (3)(4)(5)(6). 60This complex feat is driven by neuronal polarization which causes an initial break in symmetry 61 within an immature neuron, seamlessly followed by the two stages of neuritogenesis: neurite 62 initiation followed by neurite elongation (4, 7, 8). Following neuronal polarization, actin 63 aggregates form the sites of primitive neurites, precursors to the axon and dendrites (4, 9, 10). At 64 these sites, actin rich filopodia and lamellipodia rapidly extend and retract before being stabilized 65 by microtubule invasion. Microtubules then drive neurite elongation as primitive neurites are lead 66 to their appropriate destinations where they differentiate into a single axon and multiple dendrites 67 (8,(11)(12)(13)(14). It is of current interest which proteins are key players in this early developmental 68 process, particularly those which are causatively mutated in neurodevelopmental disorders. 69Following neurite formation, dendrites mature and develop intricately branched, complex 70 structures that form synaptic contacts with neighboring neurons that, when formed correctly, lead 71 to functional connectivity (1, 2, 15). The sit...

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“…Microtubules are among the most prominent structural components found in growing and mature neuritic projections [4][5][6]. The microtubule-associated protein tau plays an important role in microtubule assembly and stabilization [7].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Tau Rescues Nogo-66-Induced Neurite Outgrowth Inhibition In Vitro

Zuo

Xiong

et al. 2016

Neurosci. Bull.

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Nogo-66 plays a central role in the myelinmediated inhibition of neurite outgrowth. Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. It remains unverified whether tau interacts directly with growth factor receptors, or engages in cross-talk with regeneration inhibitors like Nogo-66. Here, we report that plasmid overexpression of tau significantly elevated the protein levels of total tau, phosphorylated tau, and microtubule-affinity regulating kinase (MARK). Nogo-66 transiently elevated the total tau protein level and persistently reduced the level of p-S262 tau (tau phosphorylated at serine 262), whereas it had little influence on the level of p-T205 tau (tau phosphorylated at threonine 205). Nogo-66 significantly decreased the protein level of MARK. Hymenialdisine, an inhibitor of MARK, significantly reduced the level of p-S262 tau. Overexpression of tau rescued the Nogo-66-induced inhibition of neurite outgrowth in neuroblastoma 2a (N2a) cells and primary cortical neurons. However, concomitant inhibition of MARK abolished the rescue of neurite outgrowth by tau in N2a cells. We conclude that dephosphorylation of tau at S262 is able to regulate Nogo-66 signaling, and that overexpression of tau can rescue the Nogo-66-induced inhibition of neurite outgrowth in vitro.

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Actin Aggregations Mark the Sites of Neurite Initiation

Cited by 18 publications

References 81 publications

Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation

Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation

14-3-3 shuttles Activity-dependent neuroprotective protein to the cytoplasm to promote appropriate neuronal morphogenesis, cortical connectivity and calcium signaling

Overexpression of Tau Rescues Nogo-66-Induced Neurite Outgrowth Inhibition In Vitro

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