The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis

Abstract

The planarian Schmidtea mediterranea maintains and regenerates all its adult tissues through the proliferation and differentiation of a single population of pluripotent adult stem cells (ASCs) called neoblasts. Despite recent advances, the mechanisms regulating ASC differentiation into mature cell types are poorly understood. Here, we show that silencing of the planarian EGF receptor egfr-1 by RNA interference (RNAi) impairs gut progenitor differentiation into mature cells, compromising gut regeneration and maintenance. We identify a new putative EGF ligand, nrg-1, the silencing of which phenocopies the defects observed in egfr-1(RNAi) animals. These findings indicate that egfr-1 and nrg-1 promote gut progenitor differentiation, and are thus essential for normal cell turnover and regeneration in the planarian gut. Our study demonstrates that the EGFR signaling pathway is an important regulator of ASC differentiation in planarians.

The pioneer factor Smed-gata456-1 is required for gut cell differentiation and maintenance in planarians

“…Our results show that Smed-gata456-1 is crucial for the regeneration, remodelling, and maintenance of gut tissue. In contrast to previous findings reported for , which are also implicated in gut regeneration (Forsthoefel et al, 2012;Barberán et al, 2016), we show that Smed-gata456-1 is not required for stem cell functionality, suggesting that 1) Smedgata456-1 is involved in the differentiation and maintenance, but not the early determination, of gut cells; and 2) the stem cell compartment is not dependent on a functional gut. Moreover, apart gata456 factors described in the planarian species Schmidtea polychroa (Martín-Durán and Romero, 2011).…”

“…Smed-gata456-1 is (Garcia-Corrales and Gamo, 1986 the gut itself. By contrast, Barberán and coworkers show that inhibition of Smed-egfr-1, which blocks the differentiation of new gut cells and leads to progressive decay of the gut, results in neoblast accumulation and increased proliferation (Barberán et al, 2016). Although these two findings appear contradictory, both are in agreement with the proposed close correlation between neoblasts and the gut.…”

“…However, it has been shown that blockade of gut cell differentiation trough Smedegfr-1(RNAi) allows the maintenance of the old gut for several weeks (Barberán et al, 2016). The rapid (8 days after last dsRNA injection in intact animals) and severe disruption of the pre-existing gut following Smed-gata456-1 inhibition suggest that Smedgata456-1 plays an additional role in the maintenance or survival of differentiated gut cells.…”

“…This graded affectation is also observed following inhibition of other genes involved in gut regeneration. For example, Smed-nkx2.2(RNAi) results in partial depletion of neoblasts exclusively in the anterior portion (Forsthoefel et al, 2012), while the reduction in size and number of secondary, tertiary, and quaternary gut branches observed after Smed-egfr-1(RNAi) is more severe in the anterior region (Barberán et al, 2016). This phenomenon may be in part attributable to the physiological gradient theory, that proposes a quantitative difference in metabolic activity along the A-P axis (Child, 1929;Blackstone, 2006), as suggested by the higher cell turnover in anterior-most regions (Eisenhoffer et al, 2008).…”

“…In situ hybridization combined with immunohistochemistry using paraffin sections was performed as described previously (Barberán et al, 2016). Mallory staining was performed as previously described (Sluys 1989).…”