Neurobiology of Disease

Department of Experimental Medicine, Section of Human Physiology, University of Genova, Italy.
Neurobiology of Disease (Impact Factor: 5.08). 04/2011; 42(1):73-84. DOI: 10.1016/j.nbd.2011.01.006
Source: PubMed


Charcot-Marie-Tooth neuropathies are frequent hereditary disorders of the nervous system and most cases remain without a molecular definition. Mutations in transcription factors have been previously associated to various types of this disease. Mice carrying a null mutation in Ebf2 transcription factor present peripheral nerve abnormalities. To get insight into Ebf2 function in peripheral nervous system, here we characterize the peripheral neuropathy affecting these mice. We first show that Ebf2 is largely expressed in peripheral nerve throughout postnatal development, its expression being not only restricted to non-myelin forming Schwann cells, but also involving myelin forming Schwann cells and the perineurium. As a consequence, the onset of myelination is delayed and Schwann cell differentiation markers are downregulated in Ebf2-/- mice. Later in development, myelin pathology appears less severe and characterized by isolated clusters of hypomyelinated fibers. However, we find defects in the nerve architecture, such as abnormalities of the nodal region and shorter internodal length. Furthermore, we demonstrate a significant decrease in axonal calibre, with a lack of large calibre axons, and a severe impairment of motor nerve conduction velocity and amplitude, whereas the sensory nerve parameters are less affected. Interestingly, a clinical case with peripheral motor neuropathy and clinical features similar to Ebf2-/- mice phenotype was associated with a deletion encompassing EBF2 human genomic locus. These findings demonstrate that Ebf2 is a new molecule implicated in peripheral nerve development and a potential candidate gene for peripheral nerve disorders.

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Available from: Veronica La Padula, May 02, 2015
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    • "PNs are characterized by abnormal signaling in the affected nerves [9], which manifests as a variety of symptoms that differ depending on the type of nerve that is damaged. Symptoms can include pain, tingling or numbness in sensory PNs [10], impaired motor ability in motor PNs [11], and autonomic dysfunction in PNs of visceral nerves [12]. Few treatments are available to help alleviate symptoms and there are no cures [2]. "
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    ABSTRACT: Axon degeneration is a feature of many peripheral neuropathies. Understanding the organismal response to this degeneration may aid in identifying new therapeutic targets for treatment. Using a transgenic zebrafish line expressing a bacterial nitroreductase (Ntr)/mCherry fusion protein in the peripheral sensory neurons of the V, VII, IX, and X cranial nerves, we were able to induce and visualize the pathology of axon degeneration in vivo. Exposure of 4 days post fertilization Ntr larvae to the prodrug metronidazole (Met), which Ntr metabolizes into cytotoxic metabolites, resulted in dose-dependent cell death and axon degeneration. This was limited to the Ntr-expressing sensory neurons, as neighboring glia and motor axons were unaffected. Cell death was rapid, becoming apparent 3-4 hours after Met treatment, and was followed by phagocytosis of soma and axon debris by cells within the nerves and ganglia beginning at 4-5 hours of exposure. Although neutrophils appear to be activated in response to the degenerating neurons, they did not accumulate at the sites of degeneration. In contrast, macrophages were found to be attracted to the sites of the degenerating axons, where they phagocytosed debris. We demonstrated that peripheral glia are critical for both the phagocytosis and inflammatory response to degenerating neurons: mutants that lack all peripheral glia (foxD3-/-; Ntr) exhibit a much reduced reaction to axonal degeneration, resulting in a dramatic decrease in the clearance of debris, and impaired macrophage recruitment. Overall, these results show that this zebrafish model of peripheral sensory axon degeneration exhibits many aspects common to peripheral neuropathies and that peripheral glia play an important role in the initial response to this process.
    PLoS ONE 07/2014; 9(7):e103283. DOI:10.1371/journal.pone.0103283 · 3.23 Impact Factor
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    • "They are implicated in various aspects of neural development, including neuronal differentiation (Dubois et al., 1998; Pozzoli et al., 2001), migration (Garcia-Dominguez et al., 2003; Garel et al., 2000) and axon fasciculation and guidance (Garel et al., 1997, 1999, 2002; Malgaretti et al., 1997; Prasad et al., 1998; Wang et al., 1997). One member of this family , Ebf2, plays an important role in neuroendocrine, olfactory, skeletal and peripheral nerve development (Corradi et al., 2003; Giacomini et al., 2011; Kieslinger et al., 2005; Wang et al., 2004). In cerebellum, Ebf2 is involved in patterning of the cortex (Chung et al., 2008; Croci et al., 2006) and Purkinje cell survival (Croci et al., 2011). "
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    ABSTRACT: Cajal-Retzius (CR) cells play a crucial role in the formation of the cerebral cortex, yet the molecules that control their development are largely unknown. Here, we show that Ebf transcription factors are expressed in forebrain signalling centres-the septum, cortical hem and the pallial-subpallial boundary-known to generate CR cells. We identified Ebf2, through fate mapping studies, as a novel marker for cortical hem- and septum-derived CR cells. Loss of Ebf2 in vivo causes a transient decrease in CR cell numbers on the cortical surface due to a migratory defect in the cortical hem, and is accompanied by upregulation of Ebf3 in this and other forebrain territories that produce CR cells, without affecting proper cortical lamination. Accordingly, using in vitro preparations, we demonstrated that both Ebf2 and Ebf3, singly or together, control the migration of CR cells arising in the cortical hem. These findings provide evidence that Ebfs directly regulate CR cell development.
    Developmental Biology 03/2012; 365(1):277-89. DOI:10.1016/j.ydbio.2012.02.034 · 3.55 Impact Factor
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