ZBP1 phosphorylation at serine 181 regulates its dendritic transport and the development of dendritic trees of hippocampal neurons

Abstract

Local protein synthesis occurs in axons and dendrites of neurons, enabling fast and spatially restricted responses to a dynamically changing extracellular environment. Prior to local translation, mRNA that is to be translated is packed into ribonucleoprotein particles (RNPs) where RNA binding proteins ensure mRNA silencing and provide a link to molecular motors. ZBP1 is a component of RNP transport particles and is known for its role in the local translation of β-actin mRNA. Its binding to mRNA is regulated by tyrosine 396 phosphorylation, and this particular modification was shown to be vital for axonal growth and dendritic branching. Recently, additional phosphorylation of ZBP1 at serine 181 (Ser181) was described in non-neuronal cells. In the present study, we found that ZBP1 is also phosphorylated at Ser181 in neurons in a mammalian/mechanistic target of rapamycin complex 2-, Src kinase-, and mRNA binding-dependent manner. Furthermore, Ser181 ZBP1 phosphorylation was essential for the proper dendritic branching of hippocampal neurons that were cultured in vitro and for the proper ZBP1 dendritic distribution and motility.

Cue-Polarized Transport of β-actin mRNA Depends on 3′UTR and Microtubules in Live Growth Cones

“…Interestingly, Src kinase dependent Vg1RBP/ZBP1 phosphorylation has been shown to be triggered in response to attractive guidance cues, is required for stimulus-induced recruitment of β-actin mRNA into axonal growth cones, and is necessary for the subsequent attractive growth cone steering (Sasaki et al, 2010 ; Welshhans and Bassell, 2011 ; Lepelletier et al, 2017 ). Perhaps counter-intuitively, however, such phosphorylation negatively regulates ZBP1 motility and Kif5 binding in neuronal dendrites (Urbanska et al, 2017 ). ZBP1 has a net retrograde flow in axons (Nalavadi et al, 2012 ) and phosphorylation of this RBP reduces its binding to β-actin mRNA (Hüttelmaier et al, 2005 ).…”

Recent advances in branching mechanisms underlying neuronal morphogenesis

“…ZBP1 binding represses β-actin mRNA translation and ensures proper distribution to sites of local synthesis, where repression is reversed by Y396 phosphorylation on ZBP1. mTORC2, Src, and mRNA binding-dependent S181 phosphorylation of ZBP1 is essential for ZBP1 mobility and distribution along dendrites and regulation of dendritic branching in hippocampal neurons 133 . An unbiased genome-wide screen identified 55 new candidate mRNA transcripts that localize specifically to dendrites of Drosophila class IV dendritic arborization sensory neurons 134 .…”

Role of dynein–dynactin complex, kinesins, motor adaptors, and their phosphorylation in dendritogenesis

“…At the molecular level, the lack of Ser181 increases the ZBP1 interaction with KIF5A. Overall, these findings suggest that ZBP1 phosphorylation at Ser181 is critical for efficient mRNA granule unloading at the destination (Urbanska et al, 2017). Studies from non‐vertebrate systems showed additional means by which kinesin‐1 contributes to dendritogenesis.…”

“…ZBP1, known mostly for its role in β‐actin mRNA transport, is critical for dendritic arbor growth (Perycz, Urbanska, Krawczyk, Parobczak, & Jaworski, 2011). We recently showed that ZBP1 is phosphorylated at Ser181 in a mammalian/mechanistic target of rapamycin complex 2‐dependent manner, and the lack of Ser181 phosphorylation increased ZBP1 mobility in dendrites (Urbanska et al, 2017). We also showed that the establishment of proper dendritic arbor morphology in developing hippocampal neurons requires ZBP1 phosphorylation at Ser181.…”