Integrin-Mediated Dendrite Branch Maintenance Requires Abelson (Abl) Family Kinases

Adolescence is characterized by increased vulnerability to developing neuropsychiatric disorders and involves a period of prefrontal cortical dendritic refinement and synaptic pruning that culminates in cytoskeletal stabilization in adulthood. The Abl-related gene (Arg) acts through p190RhoGAP to inhibit the RhoA GTPase and stabilize cortical dendritic arbors beginning in adolescence. Cortical axons, dendrites, and synapses develop normally in Argdeficient (arg ؊/؊ ) mice, but adult dendrites destabilize and regress; thus, arg ؊/؊ mice present a model of adolescent-onset dendritic simplification. We show that arg ؊/؊ mice are impaired in a reversal task and that deficits are grossly exacerbated by low-dose cocaine administration. Although ventral prefrontal dopamine D2 receptor levels predict ''perseverative'' error counts in wild-type mice, no such relationship is found in arg ؊/؊ mice. Moreover, arg ؊/؊ mice are insensitive to the disruptive effects of the D2/D3 antagonist haloperidol in reversal but show normal sensitivity to its locomotor-depressant actions. Arg deficiency and orbitofrontal cortical Arg inhibition via STI-571 infusion also enhance the psychomotor stimulant actions of cocaine. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure.A dolescence is a critical period of maturation for corticostriatal neurocircuitry and is characterized by increased risk taking, novelty seeking, and vulnerability to addictive drugs that, with repeated use, are associated with cognitive dysfunction in adulthood (1-3). In utero cocaine exposure has limited effects on cognitive performance in adult rodents (4-6), but adolescent and adult cocaine use is associated with poor inhibitory control, inflexible behavior, and drug-related compulsivity. Here, we use an animal model of late-onset dendritic simplification to test the hypothesis that the transition from dendritic refinement and synaptic pruning processes that occur in the adolescent prefrontal cortex (PFC), to the dendrite stabilization processes occurring in the adult PFC, is a period of vulnerability to cocaine.Numerous proteins regulate cortical dendrite development; to date, however, only a few have been implicated in cytoskeletal stability in adolescence and adulthood, serving primarily to antagonize inherent cytoskeletal retraction machinery. For example, activation of the master cytoskeletal regulator, RhoA (Rho), induces neurite retraction, a process required for pruning and refining neuronal connections during development. Rho activation in mature neurons, however, leads to synapse loss and dendritic regression in a wide variety of experimental systems (7-9). Recent studies have identified a Rho inhibitory pathway involving integrin adhesion receptors, the Abl family tyrosine kinase, Arg, and the Rho inhibitor, p190RhoGAP, that acts in dendritic spines of late adolescent mice to maintain synapses and promote dendrite stabi...

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“…1C). This finding is consistent with age-related spine and basal dendrite regression in arg Ϫ/Ϫ mice (11,19,20).…”

Section: Prefrontal Postsynaptic Density Protein 95 and Dopamine Recesupporting

confidence: 89%

“…1C). This finding is consistent with age-related spine and basal dendrite regression in arg Ϫ/Ϫ mice (11,19,20).Arg Deficiency Impairs Inhibitory Control. Adult arg Ϫ/Ϫ mice were first trained to respond (nose poke) on one of three nose poke recesses in operant conditioning chambers to obtain food rein-…”

supporting

confidence: 86%

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Gourley

Koleske

Taylor

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…All methods used in this article are routinely used in our laboratories and are thus referenced (7,8,24,29) and are described in SI Materials and Methods. For protein interactions, standard coimmunoprecipitation experiments and ubiquitination assays were used as previously described (7,8).…”

Section: Methodsmentioning

confidence: 99%

“…Protein identity was determined by the software program Sequest (Thermo Finnigan). Conditional c-Abl knockouts were used, and MPTP intoxication studies and assessments in mice were performed as previously described (24,29).…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Ko¹,

Lee²,

Shin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

239

291

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Mutations in PARK2/Parkin, which encodes a ubiquitin E3 ligase, cause autosomal recessive Parkinson disease (PD). Here we show that the nonreceptor tyrosine kinase c-Abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin E3 ligase activity and protective function. c-Abl is activated by dopaminergic stress and by dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium (MPP + ) in vitro and in vivo by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), leading to parkin inactivation, accumulation of the parkin substrates aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FBP1), and cell death. STI-571, a c-Abl-family kinase inhibitor, prevents the phosphorylation of parkin, maintaining parkin in a catalytically active and protective state. STI-571's protective effects require parkin, as shRNA knockdown of parkin prevents STI-571 protection. Conditional knockout of c-Abl in the nervous system also prevents the phosphorylation of parkin, the accumulation of its substrates, and subsequent neurotoxicity in response to MPTP intoxication. In human postmortem PD brain, c-Abl is active, parkin is tyrosine-phosphorylated, and AIMP2 and FBP1 accumulate in the substantia nigra and striatum. Thus, tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modification that inhibits parkin function, possibly contributing to pathogenesis of sporadic PD. Moreover, inhibition of c-Abl may be a neuroprotective approach in the treatment of PD.is a common neurodegenerative disorder characterized by the loss of dopamine (DA) neurons and protein accumulation in intracellular inclusions designated as Lewy bodies and Lewy neurites (1). Although the majority of PD is sporadic in nature, rare familial mutations are providing insight into this chronic, progressive neurodegenerative disease. Mutations in α-synuclein and LRRK2 cause autosomal-dominant PD, whereas mutations in DJ-1, PINK1, and parkin result in autosomal-recessive PD (2). Parkin mutations are the most common cause of autosomal-recessive PD and, for the most part, PD due to parkin mutations is indistinguishable from sporadic PD (3). Parkin is a ubiquitin E3 ligase, and familial mutations are thought to impair the E3 ligase activity of parkin (4, 5).Parkin ubiquitinates proteins via monoubiquitination or polyubiquitination using either lysine 48 (K48) or lysine 63 (K63). Monoubiquitination by parkin is thought to regulate receptor trafficking (6). Polyubiquitination by parkin via K48 is thought to mediate proteasomal degradation (7,8), whereas polyubiquitination by K63 may be involved in inclusion formation (9). Parkin's differential ubiquitination properties are likely to be regulated by different ubiquitin-conjugating E2s and other associated proteins or regulatory processes (3). A number of putative parkin substrates have been identified (for a review, see ref.3). Aminoacyl-tRNA synthetaseinteracting multifunctional protein type 2 (AIMP2) (p38/JTV-1) and fuse-binding protein 1 (FB...

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“…Abl‐mediated phosphorylation also controls the stability of dendrite branching in mice, as reduction of kinase levels is accompanied by decreased branching in early adulthood (Moresco et al. 2005). …”

Section: Introductionmentioning

confidence: 99%

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Franco-Villanueva

Antón

2015

Brain and Behavior

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IntroductionNeuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin‐binding molecule WIP (Wiskott‐Aldrich syndrome protein [WASP]‐interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin‐nucleation‐promoting factor neural WASP (N‐WASP) during neuritic differentiation, its implication in signal transduction remains unknown.MethodsUsing primary neurons from WIP‐deficient and wild‐type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.ResultsHere, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)‐p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)‐Akt pathway, but to reduced phosphorylation of the S6K residues Ser411 and Thr389. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP‐deficient neurons. Moreover, the preferential co‐distribution of phospho‐S6K with polymerized actin is altered in WIP‐deficient neurons.ConclusionThese experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.

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Integrin-Mediated Dendrite Branch Maintenance Requires Abelson (Abl) Family Kinases

Cited by 134 publications

References 90 publications

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

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