unc-37/Groucho and lsy-22/AES repress Wnt target genes in C. elegans asymmetric cell divisions

Abstract

AbstractAsymmetric cell division (ACD) is a fundamental mechanism of cell fate specification and adult tissue homeostasis. In C. elegans, the Wnt/β-catenin asymmetry (WβA) pathway regulates ACDs throughout embryonic and larval development. Under control of Wnt ligand-induced polarity, the transcription factor POP-1/TCF functions with the coactivator SYS-1/β-catenin to activate gene expression in the signaled cell or, in absence of the coactivator, to repress Wnt target genes in the unsignaled daughter cell. To date, investigation of Groucho function in WβA is lacking, and the function of LSY-22/AES has only been evaluated in C. elegans neurons. Further, conflicting evidence shows TCF utilizing Groucho-mediated repression may be either aided or repressed by AES addition. Here we demonstrate a genetic interaction between Groucho corepressors and POP-1/TCF in the distal tip cells (DTCs), seam cells (SCs) and embryonic endoderm development. In the DTCs, signaled cell fate increases after individual and double Groucho loss of function, representing the first demonstration of Groucho function in wildtype WβA ACDs. Further, WβA target gene misexpression occurs more frequently than DTC fate changes, suggesting derepression generates an intermediate cell fate. In the SCs, loss of UNC-37/Groucho or LSY-22/AES in a POP-1/TCF hypomorphic background enhances SC expansion and target gene misregulation. Moreover, while POP-1/TCF depletion in lsy-22/AES nulls yielded an expected increase in SCs we observed a surprising SC decrease in unc-37/Groucho nulls subjected to POP-1/TCF depletion. This phenotype correlates with UNC-37/Groucho regulation of pop-1/tcf expression since POP-1/TCF levels are increased in unc-37/Groucho null SCs. Lastly, Groucho functions in embryonic endoderm development since we observe ectopic endoderm transgene expression in unc-37/Groucho and lsy-22/AES knockdown in a HDA-1 background. Together, these data indicate Groucho-mediated modulation of cell fate via regulation of POP-1/TCF repression is widespread in WβA ACDs and suggests a novel role of LSY-22/AES as a bona fide TCF repressor.