The E‐cadherin‐Wnt‐mir‐994 Axis Repurposes a Cadherin Switch for Niche Robustness and Germline Stem Cell Maintenance

ABSTRACT

The resilience and robustness of the stem cell niche are critical for long‐term tissue homeostasis, yet the molecular circuits that ensure this stability remain poorly understood. In the Drosophila ovarian germline stem cell niche, we investigate this fundamental question through the lens of adhesion, focusing on the role of N‐cadherin in the somatic inner germarial sheath (IGS) cells. While the specific loss of N‐cadherin alone is inconsequential, we discover that it becomes essential upon the loss of E‐cadherin, revealing a critical, context‐dependent function. This functional interplay is governed by a precise molecular circuit wherein E‐cadherin cell‐autonomously represses N‐cadherin expression via a linear Wnt‐ mir‐994 signalling axis. Strikingly, this regulatory relationship constitutes a cadherin switch, which is repurposed within the niche not to promote dispersal, but to enforce resilience. The E‐cadherin‐to‐N‐cadherin switch acts as a vital compensatory mechanism: the ectopic upregulation of N‐cadherin upon E‐cadherin depletion is essential to maintain IGS cell survival and their long cellular processes, thereby rescuing niche integrity and preventing GSC loss. Our study defines the function for N‐cadherin in IGS cells, unveils the E‐cadherin‐Wnt‐ mir ‐ 994 ‐N‐cadherin axis and demonstrates the repurposing of a classic developmental module as a robustness circuit to safeguard the stem cell niche. This repurposed cadherin switch reveals an axis for targeting the resilience of niche‐stem cell interplay, and also informs new strategies for stabilizing niche environments in regenerative medicine or targeting the resilient cancer stem cell microenvironment.