Scientists from the Max F. Perutz Laboratories (MFPL) of the University of Vienna and the Medical University of Vienna have identified a specific enzyme, histone deacetylase 2 (HDAC2), as essential for brain development. The findings published in Development are important to advance the development of new drugs to treat neurological diseases.
A group of proteins, the histone deacetylases (HDACs), have been on the watch list of scientists worldwide for more than two decades. This attention is owed to their important function in epigenetics: histone deacetylases coordinate the transcription of genetic information and play an important role in the development of diseases such as cancer and neurodegenerative disorders.
HDACs inhibitors have already been applied therapeutically. However, recent studies show that the 18 variants of HDACs known in humans have individual roles in different cell types. Christian Seiser and his team at the Max F. Perutz Laboratories (MFPL) of the Medical University of Vienna, for example, recently demonstrated that deactivating HDAC1 actually accelerates skin tumor development -- a vital finding that has to be taken into account when developing new drugs to treat skin tumors.
HDAC2 is crucial for survival
In their new study supported by the Austrian Genome research program GEN-AU and the FWF Christian Seiser and his team show that HDAC2 plays a key role in brain development. They investigated the function of the homologs HDAC1 and HDAC2, which have overlapping functions, by completely or partly ablating these enzymes. These two variants had already shown to be important for the development of a normal brain structure during embryogenesis. Indeed, mice did not survive the embryonic stage when both HDAC1 and HDAC2 were completely ablated.
However, in the following experiments it became clear that HDAC2 plays the crucial role in brain development: When HDAC2 function was only partly and HDAC1 function completely ablated, the organisms were viable and fertile. While vice versa, when HDAC2 function was totally and HDAC1 function only partly ablated, the offspring died within one day after birth. These mice were also found to have excessive levels of an enzyme called protein kinase C delta -- later shown to be the reason for the impaired proliferation of progenitor cells into brain cells.
"The neonatal brain is smaller and shows less cell proliferation," explains first author Astrid Hagelkruys, who had successfully defended her PhD just a few days after the paper was accepted by Development. It is still unclear why the offspring die shortly after birth. It is possible that the occurring neurological defects influence, for example, coordination and olfactory recognition which may make the newborns unable to find the way to the mother who could provide them with food.
The impaired cell proliferation and differentiation could be restored by inhibiting or deactivating protein kinase C delta. This data indicates that HDAC2 plays a unique role in controlling cell fate during brain development by regulating key factors such as protein kinase C delta.
Results are important for the development of neurotherapeutic drugs HDAC inhibitors have shown beneficial effects in animal models for the treatment of Alzheimer's disease and Parkinson's disease and they are already approved for the treatment of epilepsy in humans. The results of the scientists from the MFPL may help the development of specific drugs to ameliorate brain function.
- A. Hagelkruys, S. Lagger, J. Krahmer, A. Leopoldi, M. Artaker, O. Pusch, J. Zezula, S. Weissmann, Y. Xie, C. Schofer, M. Schlederer, G. Brosch, P. Matthias, J. Selfridge, H. Lassmann, J. A. Knoblich, C. Seiser. A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog. Development, 2014; 141 (3): 604 DOI: 10.1242/dev.100487
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