Nicoletta Landsberger
Nicoletta Landsberger
affiliation: Università dell'Insubria
research area(s): Molecular Biology, Neuroscience
Course: Neurobiology
University/Istitution: Università dell'Insubria
1988−1989: First degree in Biological Science University of Milan.
1989−1992: Ph.D in Cellular and Molecular Biology.
1993−1997: PostDoc fellow in Dr. Alan P. Wolffe's laboratory at the National Institute of Child Health and Human Development, NIH, Bethesda, USA.
1998−2004: University Researcher in Molecular Biology at the Department of Structural and Functional Biology, University of Insubria, Varese, Italy.
2005−2009: Associate professor in Molecular Biology at the Department of Structural and Functional Biology, University of Insubria, Varese, Italy.

From September 2010 she is supervising the Laboratory of Genetic and Epigenetic Control of Gene Expression at the Department of Structural and Functional Biology, Busto Arsizio, University of Insubria and the San Raffaele Rett Research Center at the Division of Neuroscience, DIBIT, San Raffaele, Milan Even though her previous research domain was in chromatin structure and gene transcription, since the last five years, the research activity supervised by N.L. is exclusively dedicated to MECP2 and CDKL5 related disorders. Related to that, in the past she has contributed to demonstrate that the repressive role of DNA methylation occurs through the formation of a repressive chromatin structure and has participated to the demonstration that MeCP2 interacts with the Sin3A/HDAC complex. More recently, her laboratory has significantly contributed to the knowledge of CDKL5. Furthermore, her group has recently identified the first kinase (HIPK2) capable of specifically phosphorylating MeCP2, both in vitro and in vivo.
In the last years the research activity supervised by N.L. was exclusively dedicated to MeCP2 and CDKL5 related disorders. In particular, she has acquired different Mecp2 mutant mouse models of RTT and developed several essential tools for studying MeCP2 and CDKL5 as antisera, expression vectors, and ShRNA reagents for both proteins and a staminal cell line devoid of CDKL5. Very recently the laboratory has mastered essential techniques as lentivirus production and infection of primary neuron cultures useful to determine the effects of MeCP2 or CDKL5 ablation/overexpression; furthermore they have acquired the capability to perform in utero and ex utero electroporation assays important to understand MeCP2 or CDKL5 functions during cortical neuronal maturation.
In the past years, her laboratory has significantly contributed to the knowledge of CDKL5 and actually is characterizing MeCP2 phosphorylation by CDKL5 and the neuronal functions of this novel kinase and the identified specific posttranslational modification of MeCP2. They are also involved in the study of the signalling pathways regulating CDKL5’s activities. Eventually, confident that in MeCP2 phosphorylation stays one of the foremost mechanisms of regulation of this protein, in the last two years, N.L. has progressively implemented the studies on MeCP2 phosphorylation. She has recently developed and/or acquired different phospho−specific antibodies and vectors expressing only phospho−mimetic or −defective forms of MeCP2 (LEMPRA vectors) and is developing novel Mecp2 knock-in mouse defective in a specific phospho-residue.
1. Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R, Scala E, Longo I, Grosso S, Pescucci C, Ariani F, Hayek G, Balestri P, Bergo A, Badaracco G, Zappella M, Broccoli V, Renieri A, Kilstrup-Nielsen C, Landsberger N. 2005. CDKL5 belongs to the same molecular pathway of MeCP2 and its responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet. 14(14):1935-46.
2,. Bertani I, Rusconi L, Bolognese F, Forlani G, Conca B, De Monte L, Badaracco G, Kilstrup-Nielsen C*, and Landsberger N*. (2006). Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. J Biol. Chem. 281, 32048-32056.
3. Marchi M, Guarda A, Bergo A, Landsberger N, Kilstrup-Nielsen C, Ratto GM, Costa M. 2007. Spatio-temporal dynamics and localization of MeCP2 and pathological mutants in living cells Epigenetics. 2(3):187-97
4. Rusconi L, Salvatoni S, Giudici L, Bertani I, Kilstrup-Nielsen N, Broccoli V, Landsberger N (2008) CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. J. Biol. Chem. 283: 30101-11.
5. Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V. (2009). CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery. Hum. Mol. Genet. 18, 4590-602.
6. Bracaglia C, Conca B, Bergo A, Rusconi L, Zhou Z, Greenberg ME, Landsberger N, Kilstrup"Nielsen C, and Soddu S. (2009) Methyl"CpG binding protein 2 (MeCP2) is phopshorylated by HIPK2 and contributes to apoptosis. EMBO reports 10: 1327-33.
7. Forlani G, Giarda E, Ala U, Di Cunto F, Salani M, Tupler R, Kilstrup-Nielsen C, Landsberger N. 2010. The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis.
Hum Mol Genet. 19(16):3114-23.
8. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G, Calcagno E, Morello N, Landsberger N, Biffo S, Pizzorusso T, Giustetto M, Broccoli V. (2011). Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 20(6) 11892-96
9. Rusconi L, Kilstrup-Nielsen C, Landsberger N. 2011. Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation. J Biol Chem. 286(42):36550-8.
10. Williamson SL, Giudici L, Kilstrup-Nielsen C, Gold W, Pelka GJ, Tam PP, Grimm A, Prodi D, Landsberger N, Christodoulou J. 2012. A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Hum Genet. 131(2):187-200.
11. Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, Landsberger N. 2012. What We Know and Would Like to Know about CDKL5 and Its Involvement in Epileptic Encephalopathy. Neural Plast. 2012:728267. Epub 2012 Jun 17.

Project Title:
Role of MeCP2 in Cell-Proliferation and Neuronal Differentiation
Mutations of the transcription factor MeCP2 cause Rett syndrome (RTT), a devastating neurological disease representing the most common genetic cause of severe mental retardation in girls worldwide.
Cardinal RTT features include cognitive and motor impairments, hand stereotypies, seizures, loss of acquired speech, heightened anxiety, breathing abnormalities, and different autonomic dysfunctions.
Importantly, RTT appears to result from impaired neuronal maturation and/or maintenance, rather than from neuronal loss. Indeed, phenotypic rescue is possible in Mecp2-null mice upon MeCP2 re-expression.
Even if these studies did not employ clinically applicable therapeutic approaches, their implication is clear: MECP2 disorders can be treated. This “proof of principle” validates the next phase of research: finding strategies to cure RTT.
Therefore the core of our proposal is the identification of MeCP2 targets that might be relevant for the pathogenesis and that can be therapeutically modulated.
Several transcriptomic experiments have been run so far to identify the consequences of MECP2 mutations on gene expression; these studies have never been applied to prenatal samples. We will perform a global gene expression analysis comparing E15 wild-type cortical gene expression to the Mecp2-null one. Within this project, the candidate will then confirm the differential expression of relevant genes by qPCR, ISH, IHC and WB. Validation studies will occur in different animal models, including Mecp2-null hemizygous males, heterozygous females, conditional mice lacking Mecp2 in specific brain area. Different
ages, from embryos to adulthood will be considered. Cellular models such as neural stem cell and primary cultures or cell-lines will be used depending on the data.
Eventually, depending on the obtained results pharmaceutical and molecular rescue experiments will be considered.
1. Chahrour M, Zoghbi HY. 2007. The story of Rett syndrome: from clinic to neurobiology. Neuron. 56(3):422-37.
2. Guy J, Gan J, Selfridge J, Cobb S, and Bird A. 2007. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 315: 1143−1147.
3. Kishi N, Macklis JD. 2010. MeCP2 functions largely cell-autonomously, but also non-cellautonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons. Exp Neurol. 222(1): 51-8.
4. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, and Zoghbi HY. 2008. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320: 1224−1229.