Abstract
Although the mechanisms that balance self-renewal and differentiation of a stem cell lineage have been extensively studied, it remains poorly understood how tissues that contain multiple stem cell lineages maintain balanced proliferation among distinct lineages: when stem cells of a particular lineage proliferate, how do the other lineages respond to maintain the correct ratio of cells among linages? Here, we show that Merlin (Mer), a homolog of the human tumor suppressor neurofibromatosis 2, is required to coordinate proliferation of germline stem cells (GSCs) and somatic cyst stem cells (CySCs) in the Drosophila testis. Mer mutant CySCs fail to coordinate their proliferation with that of GSCs in multiple settings, and can be triggered to undergo tumorous overproliferation. Mer executes its function by stabilizing adherens junctions. Given the known role of Mer in contact-dependent inhibition of proliferation, we propose that the proliferation of CySCs are regulated by crowdedness, or confluency, of cells in their lineage with respect to that of germline, thereby coordinating the proliferation of two lineages.
Highlights
The balance between stem cell self-renewal and differentiation is critical for maintenance of functional tissues
Merlin (Mer) is a homolog of the neurofibromatosis 2 (Nf2) tumor suppressor gene, which is mutated in a rare cancer neurofibromatosis type 2, characterized by central and peripheral nervous system tumors derived from Schwann cells[8, 9]
Mer protein localizes to the cell cortex of somatic cyst stem cells (CySCs) and cyst cells (CCs) at the apical tip of the Drosophila testis
Summary
The balance between stem cell self-renewal and differentiation is critical for maintenance of functional tissues. Tissues that contain multiple stem cell lineages must further coordinate the proliferation rates among distinct lineages such that the correct ratio of all cell types is maintained within the tissue. The lack of coordination among multiple stem cell lineages may cause unbalanced proliferation of a certain lineage with respect to others, leading to disruption of tissue architecture Such disruption can be a triggering event for more complex pathologies, including tumorigenesis and tissue degeneration. Mer is required for tissue homeostasis in the liver, where Mer mutation leads to overgrowth of the tissue[13, 14] It is not well understood how the contact inhibition mechanism elucidated through cell culture models applies to in vivo settings, where multiple cell types are organized into complex tissue architecture. Our work provides insights into how tissues composed of multiple cell types might achieve coordinated proliferation rates to maintain tissue homeostasis
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