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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/648

Authors: Cobolli Gigli, Clementina
Title: Lack of Mecp2 interferes with cortical progenitors proliferation and differentiation.
Abstract: Rett syndrome (RTT) is a progressive neurological disorder affecting 1 in 10.000 live female births; nowadays is the most common genetic cause of intellectual disability in females. RTT is characterized by a normal pregnancy period and an apparently normal early post-natal phase. Around 6-18 months of life children lose all the previously acquired skills and manifest overt symptoms (as autistic features, loss of purposeful hand use, respiratory abnormalities and motor dysfunctions). Classical RTT cases are linked to mutations in the X-linked MECP2 gene that encodes for the Methyl-CpG-Binding Protein 2 (MeCP2), a multi-functional protein ubiquitously expressed in the body. The apparently normal early post-natal period explains why most of the studies in the RTT field focused post-natally, while the role of the protein during early development was only partially investigated. However, nowadays, many evidences demonstrating the presence of earlier symptoms in both girls and RTT animal models are arising. Therefore, we decided to investigate the role of Mecp2 during early/embryonic cortical development, as the cerebral cortex morphology is altered in RTT and patients manifest cognitive impairments. We demonstrated that E15.5 cortices are characterized by an altered expression profile suggestive of a delay in neuronal maturation. Thus, we analysed neuroprogenitors highlighting that Mecp2 absence slightly alters the cell cycle progression, lengthening the permanence of cells in the G1 phase. This possibly impairs the proper definition of cell fate, as Mecp2 null embryonic cortices are characterized by the increment of cells transitioning from progenitors to post-mitotic neurons. Interestingly, the altered switch is in line with the maturation delay suggested by our transcriptional analysis, as the impaired fate definition can delay the expression of genes characterizing more mature cells as different glutamate receptors and ion channels subunits. Cells, delayed in their maturation since early/embryonic phases, are not properly responding to external stimuli, resulting in their defective integration in the forming network, which is a feature common to many autistic spectrum disorders. Our data represent a first evidence of the importance of Mecp2 during embryonic development and suggest that the phenotype characterizing RTT patients is due to the sum of different alterations occurring since embryonic development and worsening through life.
Keywords: Corticogenesis, Rett syndrome, progenitors, neurogenesis
Issue Date: 2015
Language: eng
Doctoral course: Neurobiologia
Academic cycle: 28
Publisher: Università degli Studi dell'Insubria
Citation: Cobolli Gigli, C.Lack of Mecp2 interferes with cortical progenitors proliferation and differentiation. (Doctoral Thesis, Università degli Studi dell'Insubria, 2015).

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