White sponge nevus (WSN) is a benign autosomal dominant disorder characterized by the formation of white spongy plaques in the oral mucosa. Keratin (KRT) 13 is highly expressed in the mucosa, and mutations in this gene have been commonly associated with WSN patients. However, it remains unknown whether there is a causal relationship between KRT13 mutations and WSN and what the underlying mechanisms might be. Here, we use mouse genetic models to demonstrate that Krt13 is crucial for the maintenance of epithelial integrity. Krt13 knockout mice show a WSN-like phenotype in several tissues, including the tongue, buccal mucosa, and esophagus. Transcriptome analyses uncover that Krt13 regulates a cohort of gene networks in tongue epithelial cells, including epithelial differentiation, immune responses, stress-activated kinase signaling, and metabolic processes. We also provide evidence that epithelial cells without Krt13 are susceptible to mechanical stresses experienced during postnatal life, resulting in unbalanced cell proliferation and differentiation. These data demonstrate that Krt13 is essential for maintaining epithelial homeostasis and loss of Krt13 causes the WSN-like phenotype in mice.

白色海绵痣 (WSN) 是一种良性常染色体显性遗传疾病，其特征是在口腔黏膜中形成白色海绵状斑块。角蛋白 ( KRT ) 13 在粘膜中高度表达，该基因的突变通常与 WSN 患者有关。然而，KRT13突变与 WSN之间是否存在因果关系以及潜在机制可能是什么仍然未知。在这里，我们使用小鼠遗传模型来证明 Krt13 对于维持上皮完整性至关重要。Krt13基因敲除小鼠在包括舌头、颊粘膜和食道在内的多种组织中显示出类似 WSN 的表型。转录组分析发现 Krt13 调节舌上皮细胞中的一组基因网络，包括上皮分化、免疫反应、应激激活激酶信号传导和代谢过程。我们还提供证据表明，没有 Krt13 的上皮细胞容易受到出生后经历的机械应力的影响，从而导致细胞增殖和分化不平衡。这些数据表明 Krt13 对于维持上皮稳态至关重要，Krt13 的缺失会导致小鼠出现类似 WSN 的表型。