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Pdx1-Cre-driven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development
Miao Zhao1, Parisa Rabieifar1, Tânia D F Costa1
1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
p21-activated kinase 4 (PAK4) is not essential for mouse pancreas development, despite causing embryonic lethality when depleted constitutively. Conditional depletion in the pancreas did not affect its structure or function, enabling future disease modeling.
Area of Science:
- Cell Biology
- Developmental Biology
- Genetics
Background:
- p21-activated kinases (PAKs) are serine/threonine kinases involved in cellular processes.
- While PAK1 and PAK3 impact pancreas function, PAK5 and PAK6 do not.
- Constitutive PAK4 depletion leads to embryonic lethality with heart and brain defects.
Purpose of the Study:
- To investigate the role of p21-activated kinase 4 (PAK4) in mouse pancreas development.
- To determine if PAK4 is essential for exocrine, endocrine, and ductal pancreas compartments.
Main Methods:
- Conditional gene depletion of PAK4 in the pancreas using Pdx1-Cre mice.
- Verification of PAK4 protein loss in knockout (KO) pancreatic tissue.
- Morphological, immunohistochemical, and quantitative analyses of pancreas compartments.
- Assessment of body weight and glucose tolerance in wild-type (WT) and PAK4 KO mice.
Main Results:
- PAK4 KO mice were born at expected Mendelian ratios.
- Pancreatic exocrine, endocrine, and ductal compartments showed normal proportions and distributions.
- No significant differences in body weight or glucose tolerance were observed between WT and PAK4 KO mice.
Conclusions:
- PAK4 is dispensable for normal mouse pancreas development.
- The generated Pdx1-Cre-driven conditional PAK4 KO mouse model is suitable for studying PAK4's role in pancreatic diseases like pancreatitis and cancer.
