Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal
Yiwei Zhang1, Shelya X Zeng1, Qian Hao2
1Department of Biochemistry & Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Abstract:
Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner. Here, we report the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and functional maintenance, using mouse lines with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells. Interestingly, deletion of MDM2 results in defects of embryonic endocrine pancreas development, followed by neonatal hyperglycemia and lethality, by inducing pancreatic progenitor cell apoptosis and inhibiting cell proliferation. However, unlike MDM2-knockout animals, mice lacking MDMX in endocrine progenitor cells develop normally. But, surprisingly, the survival rate of adult MDMX-knockout mice drastically declines compared to control mice, as blockage of neonatal development of endocrine pancreas by inhibition of cell proliferation and subsequent islet dysfunction and hyperglycemia eventually lead to type 1 diabetes-like disease with advanced diabetic nephropathy. As expected, both MDM2 and MDMX deletion-caused pancreatic defects are completely rescued by loss of p53, verifying the crucial role of the MDM2 and/or MDMX in regulating p53 in a spatio-temporal manner during the development, functional maintenance, and related disease progress of endocrine pancreas. Also, our study suggests a possible mouse model of advanced diabetic nephropathy, which is complementary to other established diabetic models and perhaps useful for the development of anti-diabetes therapies.
Insights
The MDM2/MDMX-p53 pathway is crucial for pancreatic islet development and function. Inhibiting MDM2 causes embryonic defects, while inhibiting MDMX leads to type 1 diabetes-like disease and nephropathy in adult mice.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Biology
Background:
- The p53 protein, a key regulator of cell fate and disease, is controlled by inhibitors MDM2 and MDMX.
- MDM2 and MDMX can act together or separately to regulate p53, especially in later development and adulthood.
- The specific roles of MDM2 and MDMX in pancreatic islet development and function remain largely unclear.
Purpose of the Study:
- To investigate the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and function.
- To examine the effects of MDM2 or MDMX deletion in pancreatic endocrine progenitor cells.
- To establish a potential mouse model for advanced diabetic nephropathy.
Main Methods:
- Utilized conditional gene-modification mouse models with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells.
- Observed embryonic development, neonatal survival, and adult health in knockout mice.
- Assessed pancreatic islet morphology, cell apoptosis, proliferation, and function.
- Confirmed the role of p53 by analyzing rescue experiments with p53 loss.
Main Results:
- Deletion of MDM2 in pancreatic progenitor cells led to embryonic endocrine pancreas developmental defects, neonatal hyperglycemia, and lethality due to increased apoptosis and inhibited proliferation.
- Mice lacking MDMX in endocrine progenitor cells initially developed normally, but adult mice showed drastically reduced survival rates, developing type 1 diabetes-like disease and advanced diabetic nephropathy.
- Loss of p53 completely rescued the pancreatic defects observed in both MDM2- and MDMX-deleted mice, confirming the pathway's critical role.
Conclusions:
- The MDM2/MDMX-p53 pathway regulates pancreatic islet development and function in a spatio-temporal manner.
- MDM2 inhibition impacts embryonic development, while MDMX inhibition leads to adult-onset diabetes and nephropathy.
- This study provides a valuable mouse model for advanced diabetic nephropathy, potentially aiding anti-diabetes therapy development.
