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Tamalin is a scaffold protein known to regulate membrane trafficking through its interaction with cytohesin-2/ARNO, guanine nucleotide exchange factor (GEF) on ADP-ribosylation factor (Arf) 1/6, and induces actin reorganization. However, the neuronal function of Tamalin is not well understood. Here, we report that Tamalin participates in neurite development through the association with exchange factor for Arf6 (EFA6A)/Arf6 signaling. In immature hippocampal neuron, Tamalin knockdown markedly reduced the dendritic outgrowth, the number of dendritic tips and the levels of filamentous actin (F-actin) and microtubule-associated protein 2 (MAP2) in dendrites. In addition, Tamalin colocalized with EFA6A and Arf6 in the dendritic shaft. Tamalin knockdown reduced the number, size, and intensity of endogenous EFA6A cluster, whereas overexpression of Tamalin showed opposite effects compared with those of knockdown. These results suggest that Tamalin is responsible for neuronal dendritic development via regulation of EFA6A/Arf6-mediated cytoskeleton dynamics., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Thymosin-betas (Tbetas) are small polypeptides with various biological functions, including cytoskeletal remodeling, angiogenesis, cellular migration, wound healing, and regulation of apoptosis. Recently, we found that Tbeta is involved in the control of programmed cell death (PCD) of motoneurons (MNs) in chick embryo, and that the anti-apoptotic action of Tbeta is independent of its actin-sequestering activity. In this study, we observed that a synthetic peptide derived from Tbeta suppressed staurosporine-induced neuronal apoptosis in vitro, and PCD of chick or rat MNs in vivo. Furthermore, inhibition of Tbeta4 in chick embryo by antibody significantly augmented the PCD of MNs, suggesting that secreted form of Tbeta is physiological regulator of PCD. Based on these findings, we propose that extracellularly secreted Tbeta is involved in the control of PCD of neurons during development, and Tbeta-derived peptides could be useful for the anti-apoptotic therapy of neuropathologies related to neuronal apoptosis.

Thymosin-betas (Tbetas) are water-soluble peptides abundantly present in the cytoplasm and extracellular compartment. The functions of Tbetas appear to be pleiotrophic, including actin-remodeling, wound healing, angiogenesis, etc. In the present study, we present the evidence that Tbetas have anti-apoptotic activity on developing chick motoneurons (MNs) in vivo. Using in ovo electroporation, we introduced three isoforms of Tbeta (Tbeta4, Tbeta10, and Tbeta15) and found the significantly diminished normal and limb bud removal (LBR)-induced programmed cell death. Such anti-apoptotic activity is independent of Tbeta's actin remodeling activity. On the other hand, overexpression of Tbetas substantially reduced early cell death initiation signal, such as phosphorylation of c-Jun. Collectively, these results suggest that Tbetas may prevent apoptosis of neurons via blockade of early apoptogenic signals independent of actin remodeling action.

The thymosin betas (Tbetas) are polypeptide regulators of actin dynamics that are critical for the growth and branching of neurites in developing neurons. We found that mRNAs for Tbeta4, Tbeta10, and Tbeta15 were highly expressed in the developing rat brain during neuritogenesis, supporting a role for the Tbetas in this process. Overexpression of the Tbetas increased the number of neurite branches per neuron in cultured hippocampal and cerebral cortex neurons, and Tbeta15 had the greatest effect. Actin binding activity appears to be essential for the branch-promoting activity of Tbetas because two mutants of Tbeta15 lacking monomeric actin binding activity failed to stimulate branch formation. We also found that transfection of siRNA against Tbeta15 reduced branching. Taken together, these data suggest that the three Tbetas, and especially Tbeta15, stimulate neurite branching during brain development.