038 Digit Tip Regeneration and Global Gene Expression Profiling in the MRL SuperHealer Mouse

Abstract

The MRL mouse is the only known strain of mouse that can regenerate cardiac lesions and completely heal ear punches without scarring. To determine if the MRL also has greater regeneration capabilities in amputated digit tips, right paw digit tips of neonatal mice were dissected, with the left front paws as uncut controls. Controls used for regeneration comparison were the DBA, B6, C3H, and 129 inbred mouse strains. Consecutive X-ray images were captured of the left and right paws at 0, 7, 14, 21, and 28 days postamputation. MRL mouse digit tips regenerated greater in comparison to all strains tested (p < 0.05). We next undertook whole genome microarray analysis to identify the genetic mechanisms that contribute to differences in digit tip regeneration. Over 400 genes out of 15,000 were significantly differentially expressed (p < 0.05) in MRL and DBA mice at day 4 in comparison to day 0 control tissue. Of these, 170 genes were upregulated and 280 were downregulated in both mouse strains. Pathway analysis reveals that genes in the BMP/TGF pathway are differentially expressed in both mouse strains (p < 0.05). Multiple differences between MRL and DBA strains were found in transcription factors that are implicated in gastrulation, including FMN2 and SHRM. Additional differentially expressed genes include NET1 in the WNT signaling pathway. Immunohistochemistry indicates that these proteins are highly expressed in the nuclei of chondrocytes in regenerating digits. We conclude that MRL mice show greater regenerative capacity to heal digit tips and that the increased regenerative capacity of MRL mice may be due to strain specific increased expression of genes involved in the WNT pathway and genes involved in embryonic pattern formation. Acknowledgments: This work was supported by Assistance Award DAMD17–03–2–0021 and is administered by the US Army Medical Research Activity, 820 Chandler St., Ft. Detrick, MD.