Table 1.
Kinase signaling pathways implicated in neurological diseases and their role in dendrite development.
| Kinase | Role in dendrite morphogenesis | Model system | Cell type/brain region | Manipulation | Phenotype | Disease association | References |
|---|---|---|---|---|---|---|---|
| ERK1/2 | Activity dependent growth through gene regulation, dendritic remodeling, phosphorylation of MAP2 | Rat; Transgenic mouse |
Hippocampal neurons; Sympathetic neurons |
Pharmacological inhibition | Loss of filopodial stability in dendritic spine formation; loss of dendritic formation | 16p11.2 CNV | Wu et al., 2001; Vaillant et al., 2002; Blizinsky et al., 2016 |
| GSK3b | Neurite growth, specification of axons | Mouse, human tau transgenic mice; postmortem brain | Cortex, spinal cord | Pharmacological inhibition | Attenuated tau hyperphosphorylation | AD | Ferrer et al., 2002; Tackenberg et al., 2013; Griebel et al., 2019 |
| FYN | Upstream of CDK5, regulation of cytoskeletal dynamics | Mouse | Hippocampal neurons | Pharmacological inhibition | Rescues synaptic depletion | AD | Rong et al., 2001; Ittner et al., 2010; Kaufman et al., 2015 |
| DYRK1A | Regulates filopodia and spine formation through phosphorylation of N-WASP, Phosphorylates tubulin | Mouse; transgenic mouse | Dissociated mouse cortical and pyramidal neurons | Overexpression; pharmacological inhibition | Overexpression reduces dendritic arbor and spine density. Thinner spines. Inhibition leads to reduced tau hyperphosphorylation and aggregates. | AD, DS, ASD | Courcet et al., 2012; Martinez de Lagran et al., 2012; Park et al., 2012; Ori-McKenney et al., 2016; van Bon et al., 2016; Dang et al., 2018; Melchior et al., 2019 |
| CaMKIIa | Stabilizes dendritic arbor, regulates synaptic strength | Mouse, Xenopus | Hippocampal neurons, optic tectal neurons |
Catalytic domain mutation (E183V) | Increased dendritic arborization and decreased dendritic spine density. | ASD | Shen et al., 1998; Wu and Cline, 1998; Küry et al., 2017; Stephenson et al., 2017; Akita et al., 2018 |
| CaMKIIb | Promotes actin polymerization increases filopodial extension, regulation of spine number and morphology through actin bundling | Rat | Hippocampus; hippocampal neurons | RNAi KD | Reduced number of mature dendritic spines | ASD | Shen et al., 1998; Fink et al., 2003; Okamoto et al., 2007; Küry et al., 2017; Akita et al., 2018 |
| PI3K | Growth and elaboration of dendrites through Pi3k-Akt-mTOR axis, polarity | Rat | Hippocampal neurons | Pharmacological Inhibition | Reduced dendritic number and crossings | ASD, AD | Jaworski et al., 2005; Jansen et al., 2015; Winden et al., 2018 |
| AKT | Growth and elaboration of dendrites through mTOR | Rat | Hippocampus | Constitutive activation | Increased arborization and increased spine size. | ASD | Jaworski et al., 2005; Jansen et al., 2015 |
| mTOR | Growth and elaboration of dendrites | Mouse | Hippocampal neurons; Olfactory bulb neurons |
RNA interference; Conditional knockout |
Simplification of dendritic arbor | Cortex structural defects; ASD | Zhou et al., 2009; Urbanska et al., 2012; Mirzaa et al., 2016; Sato, 2016; Skalecka et al., 2016 |
| PAK1/2 | Regulation of spine size through inactivation of cofilin | Mouse; rat | Hippocampus | Knockout | Decreased number of immature dendritic spines | ASD, ID | Asrar et al., 2009; Harms et al., 2018; Horn et al., 2019; Kernohan et al., 2019 |
| MET | Dendritic complexity, spine morphogenesis | Mouse, transgenic mouse | Hippocampal neurons | Overexpression; RNAi KD | Overexpression Increases dendritic spine density, dendritic intersections. RNAi reduces dendritic spine density and branches. | ASD | Campbell et al., 2007; Thanseem et al., 2010; Qiu et al., 2014 |
| TAOK2 | Basal dendrite development in cortical neurons, dendritic spine formation through septin 7 | Mouse, rat | Cortical neurons; hippocampal neurons | RNAi KD, knockout | Reduced basal dendrite number and complexity; reduction in mature dendritic spines. | ASD, AD, 16p11.2 CNV | de Anda et al., 2012; Tavares et al., 2013; Yadav et al., 2017 |
| CDKL5 | Dendritic complexity | Mouse | Cortical neurons | Knockout | Reduction in spine density, spine stability and PSD95 puncta | CDKL5 Syndrome, ID |
Weaving et al., 2004; Bahi-Buisson et al., 2012; Fuchs et al., 2014; Sala et al., 2016; Baltussen et al., 2018; Tang et al., 2019 |
| LRRK2 | Maintenance of dendritic length and branching | Mouse, Drosophila | Cortical neurons, slices, sensory neurons | Mutation G2019S | Mislocalized tau in dendrites leading to dendritic degeneration. Phosphorylated α-synuclein accumulation | PD | MacLeod et al., 2006; Lin et al., 2010; Di Maio et al., 2018 |
| PINK1 | Dendritic growth and arborization | Mouse | Primary cortical and midbrain dopaminergic neuron | Overexpression; knockout | Increased dendritic length on overexpression. Knockout causes dendritic length reduction. | PD | Valente et al., 2004; Dagda et al., 2014 |
| ULK4 | Pseudokinase, promotes microtubule acetylation; dendritic arborization | Mouse | Cortical neurons | Knockdown | Impaired neuritogenesis. | SZ | Lang et al., 2014, 2016; Liu et al., 2016 |