Wapl-flox Mouse

Wapl, short for wings apart-like protein homolog, is a crucial factor associated with the Cohesin complex. The Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or SA1), topologically entraps sister DNA molecules for sister chromatid cohesion in S-phase. Wapl's key function is to bind the Cohesin complex, inducing its disassociation from mitotic chromosomes to enable proper sister chromatid resolution and separation, ensuring accurate chromosome segregation [1]. It also plays roles in regulating 3D genome folding, enhancer-promoter interactions, and gene expression, and is involved in processes like neural wiring and oocyte meiotic progression [2,3,4,7].

In Nipbl+/- mouse models, which mimic Cornelia de Lange syndrome due to NIPBL haploinsufficiency, decreasing Wapl dosage was found to partially correct embryonic growth and brain transcriptome phenotypes. This suggests that Wapl mutations might also contribute to human diseases, as the patterns of gene dysregulation in WaplΔ/+ embryonic mouse brain were highly similar to those in Nipbl heterozygotes [6]. In WAPL overexpressing mice (WAPL Tg mice), CIN lesions developed without HPV E6/E7, indicating WAPL's role in cervical cancer development by increasing estrogen receptor 1 (ESR1) sensitivity through activating MACROD1, leading to the expression of MYC and Cyclin D1 [5]. In porcine and mouse oocytes, WAPL depletion led to accelerated meiotic progression, compromised spindle assembly and chromosome alignment, highlighting its role in oocyte meiotic progression through maintaining BUB3 protein levels and spindle assembly checkpoint (SAC) activity [7].

In conclusion, Wapl is essential for accurate chromosome segregation, 3D genome organization, gene expression regulation, and normal development. Mouse models, such as WAPL Tg mice, Nipbl+/- mice with Wapl dosage reduction, and WAPL-depleted oocyte models, have been instrumental in uncovering Wapl's role in diseases like cervical cancer and potential contributions to human syndromes, as well as its function in oocyte meiosis. These studies provide insights into the molecular mechanisms underlying these biological processes and disease conditions.