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Although neurons execute a cell intrinsic program of axonal growth during development, following the establishment of connections, the developmental growth capacity declines. Besides environmental challenges, this switch largely accounts for the failure of adult central nervous system ( CNS) axons to regenerate. Here, we discuss the cell intrinsic control of axon regeneration, including not only the regulation of transcriptional and epigenetic mechanisms, but also the modulation of local protein translation, retrograde and anterograde axonal transport, and microtubule dynamics. We further explore the causes underlying the failure of CNS neurons to mount a vigorous regenerative response, and the paradigms demonstrating the activation of cell intrinsic axon growth programs. Finally, we present potential mechanisms to support axon regeneration, as these may represent future therapeutic approaches to promote recovery following CNS injury and disease. [ABSTRACT FROM AUTHOR]

Presynaptic differentiation of axons plays a fundamental role in the establishment of neuronal connectivity. However, the mechanisms that govern presynaptic differentiation in the brain remain largely to be elucidated. We report that knockdown of the transcription factor MEF2A in primary neurons and importantly in the rat cerebellar cortex in vivo robustly increases the density of orphan presynaptic sites. Remarkably, the sumoylated transcriptional repressor form of MEF2A drives the suppression of orphan presynaptic sites. We also identify the gene encoding synaptotagmin 1 (Syt 1), which acts locally at presynaptic sites, as a direct repressed target gene of sumoylated MEF2A in neurons, and demonstrate that repression of Sytl mediates MEF2A-dependent elimination of orphan presynaptic sites. Finally, we uncover a role for the MEF2A-induced elimination of orphan presynaptic sites in the accumulation of presynaptic material at large maturing presynaptic boutons. Collectively, these findings define sumoylated MEF2A and Sytl as components of a novel cell-intrinsic mechanism that orchestrates presynaptic differentiation in the mammalian brain. Our study has important implications for understanding neuronal connectivity in brain development and disease. [ABSTRACT FROM AUTHOR]

Axon branching is a complex morphological process, the regulation of which we are just beginning to understand. Many factors known to be important for axon growth and guidance have emerged as key regulators of axon branching. The extrinsic factors implicated in axon branching include traditional axon guidance cues such as the slits, semaphorins, and ephrins; neurotrophins such as BDNF; the secreted glycoprotein Wnt; the extracellular matrix protein anosmin-1; and certain transmembrane cell adhesion molecules—as well as sensory experience and neuronal activity. Although less is known about the intracellular control of axon branching, in recent years significant advances have been made in this area. Kinases and their regulators, Rho GTPases and their regulators, transcription factors, ubiquitin ligases, and several microtubule and actin-binding proteins are now implicated in the control of axon branching. It is likely that many more branching regulators remain to be discovered, as do the links between extrinsic cues and intracellular signaling proteins in the control of axon branching. [ABSTRACT FROM PUBLISHER]

Abstract: The transcriptional regulator SnoN plays a fundamental role as a modulator of transforming growth factor beta (TGFβ)-induced signal transduction and biological responses. In recent years, novel functions of SnoN have been discovered in both TGFβ-dependent and TGFβ-independent settings in proliferating cells and postmitotic neurons. Accumulating evidence suggests that SnoN plays a dual role as a corepressor or coactivator of TGFβ-induced transcription. Accordingly, SnoN exerts oncogenic or tumor-suppressive effects in epithelial tissues. At the cellular level, SnoN antagonizes or mediates the ability of TGFβ to induce cell cycle arrest in a cell-type specific manner. SnoN also exerts key effects on epithelial-mesenchymal transition (EMT), with implications in cancer biology. Recent studies have expanded SnoN functions to postmitotic neurons, where SnoN orchestrates key aspects of neuronal development in the mammalian brain, from axon growth and branching to neuronal migration and positioning. In this review, we will highlight our understanding of SnoN biology at the crossroads of cancer biology and neurobiology. [Copyright &y& Elsevier]

Malignant gliomas, including glioblastoma multiforme, constitute the mostcommonand aggressive primary brain tumors in adults. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays an essential role in glioblastoma pathogenesis downstream of the major oncogenic protein epidermal growth factor receptor variant III (EGFRvIII). However, the critical gene targets of STAT3 that mediate EGFRvIII-induced glial transformation have remained unknown. Here, we identify inducible nitric oxide synthase (iNOS) as a novel target gene of STAT3 in EGFRvIII-expressing mouse astrocytes. Endogenous STAT3 occupies the endogenous iNOS promoter and stimulates iNOS transcription in EGFRvIII-expressing astrocytes. STAT3 does not appear to control iNOS transcription in astrocytes deficient in the major glioblastoma tumor suppressor protein phosphatase and tensin homolog (PTEN), suggesting that STAT3 regulates iNOS transcription specifically in EGFRvIII-expressing astrocytes. Importantly, inhibition of iNOS by distinct approaches, including knockdown by RNA interference, reduces cell population growth and invasiveness of EGFRvIII-expressing astrocytes. In addition, upon iNOS knockdown or administration of a small-molecule inhibitor of iNOS, EGFRvIII-expressing astrocytes form smaller tumors in vivo. These findings suggest that inhibition of iNOS may have potential therapeutic value for EGFRvIII-activated brain tumors. [ABSTRACT FROM AUTHOR]

The highly specialized morphology of a neuron, typically consisting of a long axon and multiple branching dendrites, lies at the core of the principle of dynamic polarization, whereby information flows from dendrites toward the soma and to the axon. For more than a century, neuroscientists have been fascinated by how shape is important for neuronal function and how neurons acquire their characteristic morphology. During the past decade, substantial progress has been made in our understanding of the molecular underpinnings of neuronal polarity and morphogenesis. In these studies, transcription factors have emerged as key players governing multiple aspects of neuronal morphogenesis from neuronal polarization and migration to axon growth and pathfinding to dendrite growth and branching to synaptogenesis. In this review, we will highlight the role of transcription factors in shaping neuronal morphology with emphasis on recent literature in mammalian systems. [ABSTRACT FROM AUTHOR]