The murine Irs1 knockout model, generated by the spontaneous Irs1S57X mutation in homozygosity, exhibits high embryonic lethality, limiting studies of adult hematopoiesis

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Introduction Insulin Receptor Substrate 1 (IRS1) is differentially expressed in hematological neoplasms suggesting a role in hematopoiesis and neoplastic transformation. Irs1 knockout mice represent a tool to investigate IRS1 function. This study compared hematological parameters of wild-type and heterozygous Irs1 S57X mice and assessed fetal lethality in homozygous mice. Methods Hematological parameters were analyzed monthly in wild-type and heterozygous mice from 8 to 22 weeks of age. Successive intercrosses failed to yield homozygous knockouts. Fetal lethality was evaluated through timed matings of heterozygous mice, with genotyping performed at various gestational stages (E9.5, E12.5, E15.5 and E18.5). Results Heterozygous mice showed no significant differences in body weight or hematological parameters compared with wild-type mice (all p-value >0.05). Homozygous Irs1 S57X mice exhibited fetal or postnatal lethality as fetuses developed until gestational stage E18.5 but were either aborted or died shortly after birth. Conclusion The Irs1 S57X mutation in heterozygosis does not alter phenotype, whereas homozygosity for Irs1 S57X is associated with markedly reduced perinatal survival, precluding adult hematopoiesis studies. Future research should focus on fetal hematopoiesis.

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