Cux1 promotes cell proliferation and polycystic kidney disease progression in an ADPKD mouse model

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1;Cux1). While kidneys isolated from newborn Pkd1 mice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1;Cux1 mice did not show any cysts. Because Cux1 are perinatal lethal, we evaluated Pkd1 mice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1;Cux1 mice, newborn Pkd1;Cux1 mice did not show any cysts. Comparison of Pkd1 and Pkd1;Cux1 mice at later stages of development showed a reduction in the severity of PKD in the Pkd1;Cux1 mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

“…An important question is whether RPGRIP1L hypomorphism causes proliferative and/or cell fate specification changes in POMC-expressing progenitors or neurons that derive from them. RPGRIP1L, a component of the centrosome, and CUX1 are implicated in the control of the cell cycle (47,48), a cellular process coordinated with ciliary formation arising from the centrosome and ciliary disassembly (49). Nevertheless, it is not clear whether the primary cilium regulates cell division.…”

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

“…Previously, significant DNA methylation alterations have been reported in CKD where more than one dmCpG site was located within CUX1 compared to individuals with no evidence of kidney disease (20). Additionally, genetic abnormalities within CUX1 have been linked to polycystic kidney disease (94) and myelodysplastic syndrome (95) in mouse models. Significant dmCpGs from Analyses 2 and 4 were located within the body of this gene which additionally showed an increase in FC in individuals with T1DM-ESKD, but this gene has not previously been explored in individuals post kidney transplant.…”

Cux1 regulation of the cyclin kinase inhibitor p27kip1 in polycystic kidney disease is attenuated by HDAC inhibitors

“…Deletion of the cathepsin-L processing site in Cux1 in Cys1 cpk mice similarly resulted in the accumulation of Cux1 (Alcalay et al, 2008). The increased expression of Cux1 in PKD is associated with increased cell proliferation and disease progression resulting from the down regulation of the cyclin kinase inhibitor p27 (Alcalay et al, 2008; Porath et al, 2017). However, forced expression of Cux1 in transgenic mice results in multiorgan hyperplasia, but does not result in cystic kidney disease (Ledford et al, 2002).…”

“…Moreover, sustained overexpression of Cux1 failed to induce rapid cyst formation after the disruption of cilia in the kidneys of adult mice (Sharma et al, 2013). To determine whether Cux1 is required for PKD progression, we crossed mice carrying a targeted deletion of Cux1 with Pkd1 CD mice, which have Pkd1 deleted in the collecting ducts (Porath et al, 2017). Mice that were homozygous mutant for both Cux1 and Pkd1 showed no cystic disease, and mice that were heterozygous for Cux1 and homo-zygous for Pkd1 showed significantly reduced cystic disease (Porath et al, 2017).…”

“…This is similar to the protracted cyst development that occurs when the Pkd1 gene is deleted in mice after a developmental switch (Piontek et al, 2007). A number of studies have shown that renal injury induces rapid cyst growth in mice when Pkd1 or cilia genes are disrupted after a developmental switch collecting duct deletion of Pkd1 and a targeted deletion of Cux1 showed that Cux1 is required for cyst growth (Porath et al, 2017). Reduced Cux1 expression in PKD mice suppresses cyst growth, and tubules in which both Cux1 and Pkd1 were deleted showed increased expression of p27 and diminished cell proliferation.…”