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Published on: December 3, 2017
Generation of mice encoding a conditional allele of Nkx2.2
Teresa L Mastracci1, Chyuan-Sheng Lin, Lori Sussel
1Department of Genetics and Development, Russ Berrie Medical Pavilion, Columbia University, 1150 St. Nicholas Ave., New York, NY, 10032, USA.
Abstract:
Nkx2.2 is a homeobox transcription factor that is expressed in the pancreas, intestine and central nervous system (CNS) during embryogenesis and in the adult. In mice, global deletion of Nkx2.2 results in cell mis-specification in each of the tissues where it is expressed, and the null mice die as neonates with severe hyperglycemia. Although a whole body knockout demonstrates the importance of Nkx2.2 in cell specification and postnatal viability, it precludes assessment of the cell-autonomous and postnatal functions of Nkx2.2. In this study we report the generation and functional characterization of mice encoding a conditional allele of Nkx2.2. We demonstrate the functional integrity of the conditional Nkx2.2 allele and report successful in vivo deletion using a pancreas-specific Cre recombinase. The pancreas-specific deletion of Nkx2.2 results in similar defects found in the Nkx2.2 null pancreas and the mice die shortly after birth, demonstrating that the neonatal lethality associated with the null allele is caused by pancreatic islet dysfunction. The generation of a conditional Nkx2.2 allele provides an important tool for identifying the cell-autonomous and postnatal activities of Nkx2.2 in establishing and maintaining cell type identities and functions in the pancreas, intestine and CNS.
Insights
Nkx2.2 is crucial for cell development in the pancreas, intestine, and CNS. Conditional Nkx2.2 deletion in the pancreas causes severe defects, leading to neonatal death from islet dysfunction.
Area of Science:
- Developmental Biology
- Genetics
- Endocrinology
Background:
- Nkx2.2 is a homeobox transcription factor vital for embryogenesis and adult function in the pancreas, intestine, and central nervous system (CNS).
- Global Nkx2.2 deletion in mice leads to cell mis-specification and neonatal lethality with hyperglycemia, but limits study of cell-autonomous functions.
- A conditional Nkx2.2 allele is needed to investigate its specific roles postnatally and within individual cell types.
Purpose of the Study:
- To generate and characterize a conditional Nkx2.2 allele for studying its cell-autonomous and postnatal functions.
- To investigate the role of Nkx2.2 in pancreatic development and function using a pancreas-specific deletion model.
Main Methods:
- Generation of mice carrying a conditional Nkx2.2 allele.
- In vivo deletion of the Nkx2.2 gene using a pancreas-specific Cre recombinase.
- Phenotypic analysis of mice with pancreas-specific Nkx2.2 deletion.
Main Results:
- The conditional Nkx2.2 allele was functionally validated.
- Successful in vivo deletion of Nkx2.2 in the pancreas was achieved using Cre recombinase.
- Pancreas-specific deletion of Nkx2.2 recapitulated defects seen in global null mice, causing neonatal death due to pancreatic islet dysfunction.
Conclusions:
- Neonatal lethality in Nkx2.2 null mice is primarily due to pancreatic islet dysfunction.
- The conditional Nkx2.2 allele is a valuable tool for dissecting the cell-autonomous and postnatal roles of Nkx2.2 in multiple tissues.
- Further research can utilize this tool to understand Nkx2.2's contribution to cell identity and function maintenance.
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