Expression of ENL YEATS domain tumor mutations in nephrogenic or stromal lineage impairs kidney development

Area of Science:

• Developmental Biology
• Cancer Biology
• Genetics

Background:

• Recurrent gain-of-function mutations in the ENL (echinoderm microtubule-associated protein-like 1) protein are found in Wilms tumor, a common pediatric kidney cancer.
• The precise role of these ENL mutations in kidney development and cancer initiation in vivo is not well understood.

Purpose of the Study:

• To investigate the pathological significance of ENL tumor (ENL^T) mutations in kidney development and tumorigenesis using mouse models.
• To elucidate the distinct mechanisms by which ENL mutations disrupt nephrogenesis in specific kidney cell lineages.

Main Methods:

• Generation of mouse models expressing heterozygous ENL^T mutations in Six2-positive (nephrogenic) and Foxd1-positive (stromal) lineages.
• Phenotypic analysis of mutant kidneys, including histological examination and assessment of developmental defects.
• Bulk and spatial transcriptomic analyses to identify gene expression changes in mutant kidney cells.

Main Results:

• Heterozygous ENL^T expression in Six2+ nephrogenic cells caused severe kidney defects, including compromised cap mesenchyme, reduced nephron formation, and cystic glomeruli, with aberrant Hox and Wnt signaling.
• ENL^T expression in Foxd1+ stromal cells led to renal capsule and cap mesenchyme expansion and dysregulated stromal gene expression, impairing stroma-epithelium crosstalk.
• Both mutant models resulted in neonatal lethality due to distinct lineage-specific kidney abnormalities.

Conclusions:

• ENL mutations disrupt distinct pathways essential for kidney development (nephrogenesis) through lineage-specific mechanisms.
• These findings provide critical insights into how ENL mutations contribute to kidney malformations and offer a basis for understanding their role in Wilms tumor pathogenesis.