Both Schwann cell and axonal defects cause motor peripheral neuropathy in Ebf2-/- mice.

Department of Experimental Medicine, Section of Human Physiology, University of Genova, Italy.
Neurobiology of Disease (Impact Factor: 5.2). 04/2011; 42(1):73-84. DOI: 10.1016/j.nbd.2011.01.006
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Veronica La Padula, May 02, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Collaborative prescribing has been proposed as an extension of practice for advanced pharmacist practitioners. A lack of research investigating how pharmacists might be most effective as prescribers in mental health was identified. To explore health professionals' and consumers' attitudes and beliefs that relate to the role of specialist mental health pharmacists working as collaborative prescribers within their advanced scope of practice in secondary care. Semistructured interviews were conducted with key informants in the New Zealand mental health sector. Participants were selected via a purposive sampling method, including health professionals (n=9) and consumers (n=3). NVivo software was used to analyze data, using a thematic analysis approach to develop a series of key themes from the interviews. Common themes were extracted, which were used to gather results and draw conclusions. The key findings include a widespread acknowledgment of the role of specialist pharmacists as collaborative prescribers in mental health and as integral members of the multidisciplinary team; however, consumers were unaware of pharmacists' role in secondary care. The role was seen to extend current practice particularly in medication management after assessment and diagnosis by a medical practitioner. Concerns regarding demonstrating competence, practitioner role/boundary confusion, insufficient training and workforce development, hesitancy by pharmacists to extend role, consumer awareness, and public perception of the traditional pharmacist role were identified. Solutions discussed included education by the profession; relationship building, training, and robust competency assessments; and a structured framework for implementing a collaborative prescribing model. This study suggests there was recognition and acceptance of the role that specialist pharmacist practitioners could play in contributing to the care of mental health consumers as collaborative prescribers; their medication expertise being regarded highly. Further research is necessary to investigate how current resource constraints will allow for collaborative prescribing to be implemented within the context of mental health practice.
    Research in Social and Administrative Pharmacy 08/2011; 8(3):179-92. DOI:10.1016/j.sapharm.2011.04.003 · 2.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD(+)-dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.
    Proceedings of the National Academy of Sciences 09/2011; 108(43):E952-61. DOI:10.1073/pnas.1104969108 · 9.81 Impact Factor