NEUROGENCREB

CREB-dependent mechanisms regulating neural stem/progenitor cell proliferation and neurogenesis

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 Obiettivo del progetto (Objective)

'Amongst the many factors regulating neural stem and progenitor cell (NSPC) proliferation, survival and differentiation, transcription factors are important factors governing gene expression in NSPCs. Several recent reports indicate that the prototypical transcription factor, cyclic-AMP Element Binding protein (CREB) displays restricted constitutively activated expression in mouse brain neurogenic zones. Germline and conditional panneuronal-specific inactivation of the Creb1 gene has shown the critical role CREB plays in neuronal survival. Closer examination of these mutant mouse brains also indicates significantly reduced cerebral size, implying CREB has a role in neurogenesis, independent of neuronal loss. Our most recent studies have made some progress toward deciphering the role of CREB in NSPCs using zebrafish as a model, where we found that we could modulate neurogenesis by modulating CREB activity. However, knowledge of the role of CREB in mammalian NSPC function is still at an early stage. Using state-of-the-art molecular genetic techniques and bioinformatics approaches, this proposal aims to thoroughly investigate the role of CREB in mammalian NSPCs in vitro and in vivo, during both mouse development and in the adult mouse brain. The study will also investigate whether CREB also has a role in the development and growth of brain tumors. Since CREB is widely expressed and many of the molecular networks between NSPCs and other stem cell types are shared, I anticipate the data obtained from this project will be applicable, not only to neural stem cells but to many other tissue-specific stem cells.'

Introduzione (Teaser)

The EU-funded project NEUROGENCREB has revealed the critical role of cyclic-AMP Element Binding protein (CREB) in health, neurodegenerative disease, cancer and neural cell survival.

Descrizione progetto (Article)

CREB is a phospho-regulated transcription factor. State-of-the-art molecular genetics techniques and bioinformatics showed that CREB has several crucial roles that include neurogenesis, neuronal survival, function, repair and differentiation. CREB acts by modulating gene expression in nerve cells for neuronal activation required in brain functions such as memory and drug addiction.

Transcription factors play a key role in initiating changes to transform normal cells into cancerous ones. Unfortunately, studies on cancer patients, animal models and cell lines have shown that CREB is implicated in cancer pathways such as PI3K. Researchers on the 'CREB-dependent mechanisms regulating neural stem/progenitor cell proliferation and neurogenesis' (NEUROGENCREB) project demonstrated through gene knockout experiments in mice the role of CREB in nerve cell survival and neurodegenerative diseases like Parkinson's.

Gliomas are aggressive brain tumours that are difficult to treat due to the disease's complexity. Patient survival in cases of high-grade glioma is as low as 14 months despite interventions that include surgery, radiation and chemotherapy.

Research funded by the Marie Curie International Reintegration Grants (IRG) revealed that CREB is hyperactivated in patients suffering from gliomas. Moreover, the aggressiveness of the glioma directly correlated with increased hyperactivity of CREB. This transcription factor was thus identified as a potential biomarker for detection and cancer treatment as part of combination drugs. Besides its importance in neuronal-specific functions, CREB is also important for neural stem progenitor cell (NSPC) survival, differentiation and proliferation.

The NEUROGENCREB project made significant contributions in elucidating the CREB-dependent mechanisms that regulate NSPC proliferation, neurogenesis, nerve cell survival and other important functions. Consequently, an insight into CREB and its role in brain tumour formation and growth could be obtained. Results could also be extrapolated to other tissue-specific stem cells.