Mechanisms Underlying the Initiation and Dynamics of Neuronal Filopodia: From Neurite Formation to Synaptogenesis - International Review of Cell and Molecular Biology - page 121

through sequences usually localized to the 3′ untranslated regions. Zip
code binding protein 1 (ZBP1) associates with β-actin mRNA and others
( Donnelly et al., 2010 ). A role for ZBP1 in the regulation of filopodia was
detected in ZBP1 knockout neurons. Interestingly, ZBP1 knockout affects
the length, but not number, of growth cone filopodia ( Welshhans and Bas-
sell, 2011 ). Fragile X mental retardation protein (FMRP) is another RNP
that has been involved in the regulation of growth cone filopodia. Knock-
out of FMRP results in increased numbers of growth cone filopodia ( Antar
et al., 2006 ). Interestingly, FMRP binds the mRNA to MAP1B ( Antar et al.,
2006 ), which negatively regulates axonal filopodia and branches ( Bouquet
et al., 2004 ). The induction of axonal filopodia by nerve growth factor is
dependent on the axonal translation of mRNAs encoding for proteins that
regulate the Arp2/3 complex (e.g. cortactin, Arp2; Spillane et al., 2012 ).
Localized protein synthesis also regulates dendritic filopodia, which serve as
precursors to the formation of postsynaptic structures termed spines . FMRP
knockout neurons exhibit increased numbers of dendritic filopodia, and
less spines ( Antar et al., 2006 ; Dictenberg et al., 2008 ). In contrast, ZBP1
positively regulates the density of dendritic filopodia ( Eom et al., 2003 ).
Calcium-calmodulin dependent kinase I (CaMKI) phosphorylates and
regulates the eukaryotic initiation factor eIF4GII, which in turn promotes
protein synthesis. In dendrites, phosphorylation of eIFGII by CaMKI in
response to activity promotes the formation of dendritic filopodia ( Srivas-
tava et al., 2012 ). Collectively, these studies indicate that localized transla-
tion of RNP-associated mRNAs in growth cones, axons and dendrites can
regulate both the number and length of neuronal filopodia.
3.5. Filopodia as Signaling Domains
Filopodia act as sensors which allow neuronal growth cones and axons
to respond to extracellular signals, and signaling initiated within a single
filopodium is sufficient to elicit a full response by the growth cone (Sec-
tion 2.2 ). Understanding the spatiotemporal aspects of signaling pathways
in filopodia will provide insights into the mechanisms used by neurons to
respond to extracellular signals. Calcium is a major regulator of the cyto-
skeleton and neuronal physiology, and growth cone filopodia represent sub-
cellular domains of localized calcium signaling. Gomez et al. (2001) found
that individual filopodia initiate calcium transients that result in the genera-
tion of more wide spread calcium signals in the growth cone. The filopodial
transients stabilized filopodia, and when experimentally elicited asymmetri-
cally across the growth cone, resulted in a redirection of axon extension