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Genetic and Epigenetic Control of Gene Expression  

Laboratory of the Genetic and Epigenetic Control of Gene Expression

Descrizione generale Even though previous research domain of Nicoletta Landsberger was in chromatin structure and gene transcription, since the last 10 years, her research activity is exclusively dedicated to MECP2- and CDKL5- related disorders. These studies have brought to several original papers and reviews. The most relevant results obtained in the last years are herein briefly summarized.

In 2011, we have collaborated to demonstrate for the first time that a defect in protein synthesis and the AKT/mTOR pathway activation exist in mouse model of RTT. The identified defect in mTOR activation and ribosomal protein S6 phosphorylation appears so far as the best readout to assess MeCP2 dependent clinical manifestations and their possible rescue.
In 2015 we have demonstrated that MeCP2 is a key modulator of transcriptional mechanisms regulating cerebral cortex development; we suggested that RTT clinical symptoms are the cumulative result of different adverse events starting even when no obvious sign of the pathology are present. In the same year we have demonstrated for the first time that MeCP2 associates with the centrosome thereby affecting several cellular centrosomal functions. Eventually, we showed that a disorganized architecture, with hypotrophic fibres and fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the central nervous system.
Concerning CDKL5, NL has largely contributed to the actual knowledge of CDKL5 functions. In particular, she has provided the first piece of evidence demonstrating the kinase activity of CDKL5 and its molecular association with MeCP2. She has contributed to describe the spatio-temporal regulation of CDKL5 in brain and to demonstrate that the kinase is regulated by neuronal activity. Eventually, she has identified some phenotypic consequences of the lack of CDKL5 in cultured primary neurons that might justify some aspects of the associated diseases and can be used as measurable outcomes.

Generally the research of the laboratory is focused on a better characterization of MeCP2 with a particular interest in understanding transcriptional defects associated with its deficiency in neuronal and non-neuronal cells. Particular interest is given to developing brain. Furthermore, confident that a “MeCP2-code” exists we are actively characterizing novel event of phosphorylation and the molecular consequences of their misregulation. Although we are very conscious of the relevance of basic research, we have recently started also some translational studies aimed at identifying molecular, cellular and pharmacological approaches useful for the treatment of MECP2- and CDKL5-disorders.


Composizione del GruppoNicoletta Landsberger (professore associato di biologia molecolare); Angelisa Frasca (PostDoc); Maria Fazzari (dottorando); Domenico Giorgio (Fellow)


Contatto: Nicoletta Landsberger e-mail: nicoletta.landsberger@unimi.it  tel:02 50330464
Ubicazione: L.I.T.A Via Fratelli Cervi 93, 20090 Segrate, MI
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