Abstract
Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumour of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.
Highlights
Stem cell populations provide the source material for future tissue generation and play an important role in the development and maintenance of many tissues
We demonstrate that a reduction or loss of Derlin activity, which is a conserved family of proteins involved in endoplasmic reticulum-associated degradation (ERAD), suppresses over-proliferation due to GLP-1/Notch gain-of-function mutations
We demonstrate that a surveillance mechanism utilized in cells to monitor and react to proteins that are not folded properly (Unfolded Protein Response-UPR) must be functioning well in order for the loss of Derlin activity to supress over-proliferation caused by glp-1/Notch gain-of-function mutations
Summary
Stem cell populations provide the source material for future tissue generation and play an important role in the development and maintenance of many tissues. The decision to self-renew or differentiate is essential for the proper development of their tissues Critical systems like this require many layers of redundancy in order to have a high level of robustness[1,2]. This way, if pressure is applied to one layer, other layers are able to ensure proper decision-making. These layers of redundancy can allow external inputs to impinge on the system, giving it the ability to adapt. Understanding these layers of redundancy will aid in research in stem cell-related diseases and in using stem cells as therapeutic agents
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