Smed-egfr-4 is required for planarian eye regeneration

Abstract

Short running title: egfr--4 in eye regeneration ABSTRACTPlanarians are amazing animals that can regenerate a whole body from a tiny piece of them thanks to their pluripotent stem cells, the neoblasts. Planarian neoblasts include both pluripotent stem cells and specialized lineage--committed progenitors that give rise to all the mature cell types during regeneration and homeostatic cell turnover in these plastic animals. Little is known, however, about the mechanisms that regulate neoblast differentiation. Recently, it has been shown that Smed--egfr--1, a homologue of the epidermal growth factor receptor (EGFR) family is required for the final differentiation of the gut progenitors into mature cells but not for their specification.As planarians have several EGFR homologues it has been proposed that they could have diverged functionally to regulate the differentiation of the different cell types found in these animals. Here, we report on the function of Smed--egfr--4 on eye regeneration. The silencing of this gene by RNAi results in animals regenerating smaller eyes compared to controls. The numbers of both eye mature cell types, photoreceptor neurons and eye--cup pigment cells, are significantly decreased in the Smed--egfr--4(RNAi) animals. In contrast, the number of eye progenitor cells expressing the specific markers Smed--ovo and Smed--sp6--9 is increased. These results suggest that Smed--egfr--4 would be required not for the specification of eye progenitor cells but rather for their final differentiation and support the idea that in planarians the EGFR pathway could play a general role regulating the differentiation of lineage--committed progenitors.

An insight into planarian regeneration

“…In addition, the numbers of mature eye‐specific cell type including photoreceptor neurons and pigment optic cup cells were significantly reduced in egfr‐4 RNAi worms, whereas the eyes progenitor cells which expressing specific markers ovo and sp6‐9 had an increased number. These results suggest that egfr‐4 is not required for the production of eye progenitor cells, but for their final differentiation (Figure 1), supporting the idea that the Egf pathway in eukaryotic cells may play a general role in regulating differentiation of progenitor cells 64 …”

“…Smed‐nrg‐7 is also expressed in the brain and regulates stem cell division and specification. Smed‐egfr‐3 and Smed‐nrg‐7 play an important role in neuron regeneration 64,71 …”

“…These results suggest that egfr-4 is not required for the production of eye progenitor cells, but for their final differentiation (Figure 1), supporting the idea that the Egf pathway in eukaryotic cells may play a general role in regulating differentiation of progenitor cells. 64 Recently, Scimone et al found that the eye regeneration process of planarians is regulated by guidepost-like cells. 65 They found a rare subpopulation of muscle like cells (defined as guidepost-like cells; expressed notum and frizzled 5/8-4) concentrated at two precise anatomical sites and intimately associated with the photoreceptor axon.…”

“…Smed-egfr-3 and Smed-nrg-7 play an important role in neuron regeneration. 64,71 Reddien et al found that hedgehog (hh) is expressed in medial cephalic ganglia neurons and its inhibition led to the expression of filament-1 (if-1) and calamari (cali) express in unidentified non-neural CNS cell type (Figure 2). This type of cells expresses homologues of astrocyterelated genes involved in neurotransmitter uptake and metabolism, as well as extended processes covering regions of high synaptic concentration.…”

High throughput expression-based phenotyping and RNAi screening reveals novel regulators of planarian stem cells

“…Planarian muscle also constitutes a major source of ECM that provides additional signals for controlling neoblast activity (Chan et al, 2021; Cote et al, 2019; Lindsay-Mosher et al, 2020). Furthermore, regional signals can guide neoblast differentiation, for example an anterior Wnt/Notum regulatory loop regulates neural progenitors (Hill and Petersen, 2015), Hedgehog signaling guides neural specification (Currie et al, 2016), EGF signals specify differentiation of intestine, eyes and other tissues (Barberan and Cebria, 2019; Barberan et al, 2016; Emili et al, 2019; Fraguas et al, 2011), and BMP specifies epidermal progenitors into dorsal versus ventral identity (Wurtzel et al, 2017). egfr-3 and its putative ligand nrg-7 are required for self-renewal during neoblast repopulation after sublethal irradiation (Lei et al, 2016).…”