Abstract
Proper axonal growth and guidance is essential for neuron differentiation and development. Abnormal neuronal development due to genetic or epigenetic influences can contribute to neurological and mental disorders such as Down syndrome, Rett syndrome, and autism. Identification of the molecular targets that promote proper neuronal growth and differentiation may restore structural and functional neuroplasticity, thus improving functional performance in neurodevelopmental disorders. Using differentiated human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs), the present study demonstrates that during early stage differentiation of human NPCs, neuron-targeted overexpression constitutively active Rac1 (Rac1CA) and constitutively active Cdc42 (Cdc42CA) enhance expression of P-Cav-1, T-Cav-1, and P-cofilin and increases axonal growth. Similarly, neuron-targeted over-expression of Cav-1 (termed SynCav1) increases axonal development by increasing both axon length and volume. Moreover, inhibition of Cav-1(Y14A) phosphorylation blunts Rac1/Cdc42-mediated both axonal growth and differentiation of human NPCs and SynCav1(Y14A)-treated NPCs exhibited blunted axonal growth. These results suggest that: (1) SynCav1-mediated dendritic and axonal growth in human NPCs is dependent upon P-Cav-1, (2) P-Cav-1 is necessary for proper axonal growth during early stages of neuronal differentiation, and (3) Rac1/Cdc42CA-mediated neuronal growth is in part dependent upon P-Cav-1. In conclusion, Cav-1 phosphorylation is essential for human neuronal axonal growth during early stages of neuronal differentiation.
Highlights
Proper axonal growth and guidance are crucial for development of functional neuronal networks
We have previously shown that SynCav1 increases dendritic growth and arborization in primary rodent neurons in vitro (Head et al, 2011), we tested whether these effects on neuroplasticity from SynCav1 could be recapitulated in human neuron progenitor cells (NPCs)
These findings demonstrate for the first time that SynCav1 increases both dendritic and axonal growth in human neurons derived from induced pluripotent stem cells (iPSCs)
Summary
Proper axonal growth and guidance are crucial for development of functional neuronal networks. Growth cones are enriched in MLRs, discrete plasmalemmal microdomains enriched in cholesterol, glycosphingolipids, and the scaffolding protein caveolin (Cav) (Sekino et al, 2007; Grider et al, 2009; Whitehead et al, 2012). Cav-1 is a cholesterol binding and scaffolding protein within MLRs that organizes signaling complexes such as Src family kinases (SFKs), cytoskeletal tethering proteins, and Rho GTPases (RhoA, Cdc, and Rac1) that regulate cytoskeletal dynamics (Head et al, 2008, 2014; Pantera et al, 2009; Berta et al, 2011; Stuermer, 2011). In vivo delivery of SynCav to the hippocampus of adult and aged mice enhanced both MLR-localized TrkB and structural neuroplasticity, improving hippocampal-dependent memory (Egawa et al, 2017; Mandyam et al, 2017). Past findings demonstrated that Cav-1 was widely involved in opioid-induced dendritic growth (Cui et al, 2017), further demonstrating a regulatory role of Cav-1 on various forms of neuroplasticity
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