Generation of mice with a conditional null allele for Wntless

Abstract

Summary The Wnt-signaling pathway is necessary in a variety of developmental processes and has been implicated in numerous pathologies. Wntless (Wls) binds to Wnt proteins and facilitates Wnt sorting and secretion. Conventional deletion of Wls results in early fetal lethality due to defects in body axis establishment. To gain insight into the function of Wls in later stages of development, we have generated a conditional null allele. Homozygous germline deletion of Wls confirmed prenatal lethality and failure of embryonic axis formation. Deletion of Wls using Wnt1-cre phenocopied Wnt1 null abnormalities in the midbrain and hindbrain. In addition, conditional deletion of Wls in pancreatic precursor cells resulted in pancreatic hypoplasia similar to that previously observed after conditional β-catenin deletion. This Wls conditional null allele will be valuable in detecting novel Wnt functions in development and disease.

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

“…Similar to β‐catenin‐LKO and LRP5‐6‐LDKO, we observed a significantly lower liver weight to body weight ratio in EC‐Wls‐KO6, 7, 14 (Fig. 2A).…”

“…Mice were fed regular chow in standard caging and kept under a 12‐hour light–dark cycle with no enrichment. Lyve1‐cre mice were purchased from Jackson Laboratories15 and bred with Wls flox/flox mice 7, 14. Lyve1‐cre +/– ;Wls flox/flox are hereafter referred to as EC‐Wls‐KO.…”

“…This also argues that most Wnts in liver physiology are canonical and act through β‐catenin. To address cell source and identification of Wnts and because there are 19 Wnts in the mammalian genome with several expressed in various hepatic cells,13 we used mice that allowed cell‐specific deletion of Wntless (Wls), a cargo receptor essential for all Wnt secretion 14. Conditional deletion of Wls from liver ECs showed no effect on zonation or LR, while its loss from macrophages did not impact zonation but marginally affected hepatocyte proliferation at 40 hours after PH 7.…”

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

“…26 Its loss prevents Wnt secretion and hence is a way to generate the Wntless phenotype. 9 Previously, use of liver-specific Wls-LKO allowed us to study any role of hepatic epithelial cellederived Wnt proteins in initiation of LR and metabolic zonation. 10 Interestingly, continued examination of b-catenin signaling, cyclin-D1 expression, and markers of S phase in the Wls-LKO mice revealed a prolonged hepatocyte proliferative program, suggesting that hepatocytes may be the source of at least some termination signal for b-catenin signaling at the time when its activation or hepatocyte proliferation is not deemed necessary anymore.…”

Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

“…In addition, in another study, Wan et al (38) observed a lower bone mass in the postnatal Col1a1-Cre;Wls CKO mutants. It should be noted that all three studies used different Wls CKO mouse models: the Maruyama et al (55) study used Wls ex2 CKO (56), Wan et al (38) used Wls ex3 CKO (57), and we used Wls ex1 CKO, in which the ATG start site was also floxed, generated by a third group (52). In view of the discrepancies among the findings, it is important to resolve any differences arising from using different mouse models to ensure that the results are truly biologically relevant.…”