UB research group describes a key gene in early brain regeneration in planarians

The planarian Schmidtea mediterranea are flatworms with bilateral symmetry used as models in the research on cell regeneration and stem cells. The paper describes the first study that relates the gene egr-4 —member of a gene family that codifies transcription factors and regulate the activity of other genes— with the process of neurogenesis in planarians.

Professor Francesc Cebrià, leader of the scientific study, affirms that “in other animals, genes egr are activated in immediate response processes such as inflammation, wound healing and stress”. “Moreover —he points out—, some of these genes also play a major role in the development of the nervous system”. The genes egr control different processes, from cell proliferation to cell survival or cell differentiation. In the case of planarians, the gene egr-4 seems to perform an early control of cell proliferation as a response to amputation, and then be involved in the early differentiation of brain during regeneration. Cebrià highlights that “as there are genes which are similar to egr-4 in other lineages —for instance the human species—, this function may be particularly interesting to understand the process of regeneration in metazoans”.

The gene egr-4: key in early phases

Authors affirm that egr-4 may play a major role in the formation of the brain primordia. By applying gene silencing techniques to experimental design, experts have delimited several periods of the regeneration process in which gene function is determinant.

Susanna Fraguas, first author of the article, explains that “the study proves that gene egr-4 is involved in the first phases of brain cell differentiation. To be exact, the gene may affect the differentiation of the brain primordia, even if other genes are also probably involved”. Susanna Fraguas details that the study wanted to decipher gene function and know which signals it activates in order to induce the differentiation of the brain primordia. If the primordia are not well-differentiated, the nervous system cannot regenerate in a correct way. Therefore, egr-4 is a key gene in early brain regeneration.

Regeneration and nervous system: a link also observed in planarians

Tissue regeneration is a highly complex process studied by international research groups in different animal models (planarian, zebra fish, newt, axoloti, Hydra, etc.). The scientific community has long postulated that the nervous system may play a determinant role in the process of regeneration in animals.

“Probably, any molecule related to the nervous systems induce cell proliferation or differentiation during regeneration”, remarks Francesc Cebrià. This is called nerve dependence of regeneration; however, Cebrià points out that “in most models, only indirect signs have been found”. Exceptionally, in the case of newts, a molecule secreted by Schwann cells has been identified; it may explain the participation of the nervous system in regeneration. “Therefore —says the expert—, the results of our study with planarians describes one of the first genes in these animals that is necessary for early brain regeneration and anterior regeneration”.

When the brain does not regenerate well

The new study strengthen the hypothesis suggested about the key role that the nervous system plays in metazoan regeneration. Furthermore, if defines a hypothetic model in which early brain regeneration is crucial to guarantee anterior regeneration in planarians. In other words, if brain is not well-regenerated, the global regeneration programme is stopped.

The main idea of the study is that gene egr-4 plays a crucial role in the differentiation of brain primordia. Primordia may synthetize a molecule that remains unknown and may promote or maintain blastema growth, the new tissue which is being regenerated. Blastema growth may depend on a factor which remains unknown that may link brain and global regeneration. “We have already observed that gene egr-4 is regulated by the epidermal growth factor receptor (EGFR) signaling pathway, so it will enable to identify also the factors that activate this pathway during anterior regeneration. In any case, “the traditional hypothesis about the dependence of regeneration and the nervous system is also proved in planarians”, concludes, Cebrià.

Reference article:

Fraguas, S.; Barberán, S.; Iglesias, M.; Rodríguez Esteban, G.; Cebrià, F. “Egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians”. Development, May 2014. Doi: 10.1242/dev.101345