For more than 15 years, TPX2 has been studied as a factor critical for mitosis and spindle assembly. These functions of TPX2 are attributed to its Ran-regulated microtubule-associated protein properties and to its control of the Aurora A kinase. Overexpressed in cancers, TPX2 is being established as marker for the diagnosis and prognosis of malignancies. During interphase, TPX2 resides preferentially in the nucleus where its function had remained elusive until recently. The latest finding that TPX2 plays a role in amplification of the DNA damage response, combined with the characterization of TPX2 knockout mice, open new perspectives to understand the biology of this protein. This review provides an historic overview of the discovery of TPX2 and summarizes its cytoskeletal and signaling roles with relevance to cancer therapies. Finally, the review aims to reconcile discrepancies between the experimental and pathological effects of TPX2 overexpression and advances new roles for compartmentalized TPX2.

Background: TPX2 is as an essential protein for mitosis, but its nuclear function is unknown. Results: TPX2 goes to DNA double strand breaks and regulates ␥-H2AX levels upon ionizing radiation. Conclusion:We discover a novel and the first nuclear function for TPX2. Significance: Our study provides new insights into the physiological and oncological roles of TPX2.

Ndel1, the mammalian homologue of the Aspergillus nidulans NudE, is emergently viewed as an integrator of the cytoskeleton. By regulating the dynamics of microtubules and assembly of neuronal intermediate filaments (IFs), Ndel1 promotes neurite outgrowth, neuronal migration, and cell integrity (1-6). To further understand the roles of Ndel1 in cytoskeletal dynamics, we performed a tandem affinity purification of Ndel1-interacting proteins. We isolated a novel Ndel1 molecular complex composed of the IF vimentin, the molecular motor dynein, the lissencephaly protein Lis1, and the cis-Golgi-associated protein ␣COP. Ndel1 promotes the interaction between Lis1, ␣COP, and the vimentin-dynein complex. The functional result of this complex is activation of dynein-mediated transport of vimentin. A loss of Ndel1 functions by RNA interference fails to incorporate Lis1/␣COP in the complex, reduces the transport of vimentin, and culminates in IF accumulations and altered neuritogenesis. Our findings reveal a novel regulatory mechanism of vimentin transport during neurite extension that may have implications in diseases featuring transport/trafficking defects and impaired regeneration.The cytoskeleton constitutes a highly organized structure formed by the interconnection of three filamentous networks (microtubules (MTs), 3 intermediate filaments (IFs), and microfilament) and their associated proteins (7-10). The dynamics of these networks regulate essential intracellular functions such as transport and trafficking and, therefore, impact on cell division, morphology, and integrity (7-10). Named according to their intermediate diameter (10 nm), IFs constitute the largest family of cytoskeletal proteins. Up to 60 genes encoding for IFs are expressed in a tissue-specific and spatio-temporal manner in mammals (7,11,12). After synthesis in the cytoplasm, a fraction of soluble IF proteins is rapidly incorporated into the polymeric filamentous network, referred to as the "insoluble" fraction (7, 12). In parallel, individual IF subunits, dimers, or small oligomers that constitute the "soluble" fraction translocate rapidly along MTs via molecular motors in structures termed particles (13,14). This model is particularly relevant for the assembly of the IF vimentin (15, 16) and more controversial in the case of neuronal IFs (NFs) (17-19).The neurofilament proteins (NF-L, NF-M, and NF-H) are the most abundant IFs in mature central nervous system neurons (12). We recently demonstrated that Ndel1, the mammalian homologue of the Aspergillus nidulans NudE, a protein implicated in nuclear distribution during hyphal growth, binds directly to the key subunit NF-L, thereby regulating NF assembly (5). Ndel1 also interacts with the Disrupted-in-Schizophrenia protein 1 (DISC1) to regulate MT dynamics during neurite outgrowth in neuroblastoma PC-12 cells and during neuronal migration in the developing cortex. Interestingly, Ndel1 associates with the molecular motors dynein/dynactin (20 -22), and numerous independent reports documented the dynein tran...

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Failure of axons to regenerate following acute or chronic neuronal injury is attributed to both the inhibitory glial environment and deficient intrinsic ability to re-grow. However, the underlying mechanisms of the latter remain unclear. In this study, we have investigated the role of the mammalian homologue of aspergillus nidulans NudE, Ndel1, emergently viewed as an integrator of the cytoskeleton, in axon regeneration. Ndel1 was synthesized de novo and upregulated in crushed and transected sciatic nerve axons, and, upon injury, was strongly associated with neuronal form of the intermediate filament (IF) Vimentin while dissociating from the mature neuronal IF (Neurofilament) light chain NF-L. Consistent with a role for Ndel1 in the conditioning lesion-induced neurite outgrowth of Dorsal Root Ganglion (DRG) neurons, the long lasting in vivo formation of the neuronal Ndel1/Vimentin complex was associated with robust axon regeneration. Furthermore, local silencing of Ndel1 in transected axons by siRNA severely reduced the extent of regeneration in vivo. Thus, Ndel1 promotes axonal regeneration; activating this endogenous repair mechanism may enhance neuroregeneration during acute and chronic axonal degeneration.