The discovery of the neural stem cells and the formation of new neurons in the adult brain opened in its moment the possibility for neural repair and the use of stem cells to future treatments in case of pathology. In this sense, the team of the researcher of the Universitat de València Sacri Ferrón (Dep. Cellular Biology/ERI Biotecmed) tries to determine the regulators that act in a coordinate way to provide the brain with a concrete number of stem cells, a crucial element for the its future use in cellular treatments. One of that regulators is the methylation of ADN, action that regulates the gene expression. Usually, methylation acts to repress the genetic transcription, modifying the gene expression in a stable basis. It is essential for the natural development of the brain.

In the work that has been just published in the magazine nature Communication, researchers have described the role of an enzyme -TET3- in the process of differentiation of the neural stem cells. The suppression of this enzyme, in a model of mouse, cancels the capacity of differentiation of the stem cells and they finally disappear irreversibly preventing the formation of new neurons in the brain of the rodent.

The usual function of the TET consists in eliminate methylations, which prevents the suppression the gene expression and controlling its expression in different cellular context. However, this study proves that, in the adult of the mammals, T3T has an unusual function: repress the transcription of the Snrpn gene, associated to the human syndrome Prader-Willi, a congenital illness that no only supposes an intellectual disability, but that also it involves physical problems -obesity among others- behavioural, and predisposes affected people to suffer cancerous tumours. This is the first time that a defect of neurogenesis that implies a gene associated to this rare illness present in 1 person in every 15.000 newborns is described.

The discovery of this unusual function of the TET3 enzyme makes way for its study in pathological cellular contexts. ‘For example, we know that neural stem cells can act as initiators of a Glioblastoma, the most common and aggressive brain tumour in humans –claims Sacri Ferrón–, and we have observed that, in the cells derived from human brain tumours, the TET3 enzyme is silenced. In addition, the SNRPN Gene –TET3 restriction site– that is associated to the Prader-Willi Syndrome in humans, also disappears in brain tumours.’

Researchers are currently working to find out whether these molecules –TET3 and SNRPN– could be intervening in the formation of brain tumours in humans. ‘In order to transform into tumours, stem cells turn off both molecules’, claims Ferrón. ‘Working to keep them in high levels could stop the cell from becoming carcinogenic.’

According to the scientist, regarding Prader-Willi patients, an incurable disease, the predisposition to grow tumours could be prevented: ‘Rescuing the SNRPN levels in patients could be the future of a therapeutic target’ she suggests.

Reference:

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn. Raquel Montalbán-Loro, Anna Lozano-Ureña, Mitsuteru Ito, Christel Krueger, Wolf Reik, Anne C. Ferguson-Smith & Sacri R. Ferrón

Nature Communications volume 10, Article number: 1726 (2019)