Pdx1-Cre-driven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development

Abstract

Constitutive depletion of p21-activated kinase 4 (PAK4) in the mouse causes embryonic lethality associated with heart and brain defects. Given that conventional gene depletion of PAK1 or PAK3 caused functional deficits in the mouse pancreas, while gene depletion of PAK5 or PAK6 did not, we asked if PAK4 might have a functional role in pancreas development. We therefore introduced conditional, Pdx1-Cre-mediated, pancreatic PAK4 gene depletion in the mouse, verified by loss of PAK4 protein expression in the pancreas. PAK4 knock-out (KO) mice were born at Mendelian ratios in both genders. Further, morphological and immunohistochemical examinations and quantifications indicated that exocrine, endocrine and ductal compartments retained the normal proportions and distributions upon PAK4 gene depletion. In addition, body weight records and a glucose tolerance test revealed no differences between WT and PAK4 KO mice. Together, this suggests that PAK4 is dispensable for mouse pancreas development. This will facilitate future use of our Pdx1-Cre-driven conditional PAK4 KO mouse model for testing in vivo potential functions of PAK4 in pancreatic disease models such as for pancreatitis and different pancreatic cancer forms.

P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades

“…Whereas PAK4 has been shown to be overexpressed in many cancers, including pancreatic cancer, and plays an important role in its growth/invasiveness (64,84), no studies have reported its expression in pancreatic acini. One study reported no expression (73), whereas another study reported PAK4 present in the pancreas, but did not state where it was in the pancreas (88). Our results demonstrate that the only Group-II PAK present in pancreatic acinar cells is PAK4.…”

The PAK Inhibitor PF-3758309 Promotes the Inhibitory Effects of Multiple Chemotherapeutic Reagents on Patient-Derived Pancreatic Cancer Cell Lines

“…This result suggests that PAK1 and PAK4 play divergent roles in the regulation or maintenance of an "epithelial" or "mesenchymal"-like state in cancer progression, and is consistent with a recent report that expression of PAK1 and PAK4 is associated with different outcomes in pancreatic cancer patients [23]. PAK1 and PAK4 also play different roles in pancreatic function, as PAK1 depletion causes deficits in glucose clearance [24], while PAK4 depletion does not alter pancreas development or function [25].…”

Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion

“…Transgenic mice with constitutive PAK4 gene depletion do not survive past embryonic day 11.5 16,32,33 ; therefore conditional gene depletion strategies have been developed in the field to study its role in different organs development 33 . Conditional depletion of PAK4 in heart, vasculature, and brain caused severe defect during embryonic development while PAK4 depletion in pancreas did not cause any evident defect in the pancreatic tissue development and function 32,33,42,43 . However, the potential function of PAK4 in mammary gland development has remained unclear.…”