What question did this study set out to answer?

To investigate the role of Wdr4 in ribosome biogenesis and intestinal stem cell homeostasis.

February 11, 2026Open Access

Wdr4 regulates ribosome biogenesis and intestinal homeostasis via let-7

KKKreeti KajalNational Chung Hsing University ERElham RastegariInstitute of Cellular and Organismic Biology, Academia Sinica WWWen-Der Wang

Key Points

To investigate the role of Wdr4 in ribosome biogenesis and intestinal stem cell homeostasis.
Identified Wdr4 as a regulator in Drosophila midgut using genetic manipulations.
Examined the interaction of Wdr4 with Mettl1 for let-7 miRNA modification.
Analyzed the effects of Wdr4/Mettl1 depletion on ISC signaling pathways.
Conducted rescue experiments with let-7 overexpression and TOR/JNK inhibition.
Wdr4 and Mettl1 depletion resulted in reduced let-7 levels and activated TOR-JNK-dMyc signaling.
Increased ribosome biogenesis and ISC overproliferation were observed upon depletion.
Rescue of defects was achieved through let-7 overexpression and pathway inhibition.
Human WDR4 and METTL1 restored ISC homeostasis in Drosophila models, demonstrating conservation of the regulatory axis.

Abstract

Abstract Proper regulation of ribosome biogenesis is essential for stem cell function and tissue homeostasis, yet its upstream control in adult intestinal stem cells (ISCs) remains unclear. Here, we identify the WD repeat protein Wdr4 as a key regulator of ISC homeostasis in the Drosophila midgut. Wdr4 cooperates with the methyltransferase Mettl1 to catalyze N⁷-methylguanosine (m⁷G) modification of let-7 miRNA. Wdr4 or Mettl1 depletion disrupts this modification, reducing let-7 levels and aberrantly activating TOR-JNK-dMyc signaling. This drives elevated ribosome biogenesis, ISC overproliferation, misdifferentiation, and intestinal dysplasia. Overexpression of let-7 , inhibition of TOR, or suppression of JNK rescues these defects. Importantly, expression of human WDR4 and METTL1, but not catalytic-dead METTL1 mutant, restores ISC homeostasis in Wdr4- and Mettl1-depleted flies, establishing a conserved Wdr4/Mettl1- let-7 -TOR-JNK axis that links miRNA modification to translational control and tissue integrity. Together, our findings uncover a previously unrecognized function of miRNA m⁷G methylation in regulating ribosome biogenesis and maintaining intestinal homeostasis.

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