Background：

• IGF1 promotes cell proliferation and differentiation in tissues such as bone and muscle, enhances cell survival by inhibiting apoptosis, regulates metabolism including glucose and lipid metabolism, and is involved in the development and function of the nervous system. Abnormal IGF1 expression or signaling is linked to various diseases: in cancer, IGF1 and its receptor IGF1R are overexpressed in many tumor cells, promoting tumor growth and progression; in metabolic diseases, IGF1 abnormalities can lead to metabolic disorders like insulin resistance and diabetes; and in nervous system diseases, IGF1 dysregulation may contribute to the development of neurodegenerative conditions such as Alzheimer's and Parkinson's disease.

Targeting strategy：

• A chimeric CDS that encodes mouse Igf1 signal peptide and human IGF1 propeptide, followed by mouse 3’UTR-STOP is inserted right after mouse Igf1 gene to replace the exon 2 of mouse Igf1 gene. The chimeric IGF1 protein expression will be driven by endogenous mouse Igf1 promoter, while mouse Igf1 gene transcription and translation will be disrupted. 

Validation：

• Mouse IGF1 was only detectable in wild-type C57BL/6JNifdc mice. Human IGF1 was exclusively detectable in homozygous B-hIGF1 mice but not in wild-type mice.

Application：

• This B-hIGF1 mice can be used to study the role of IGF1 in various physiological and pathological processes, such as cancer, metabolic disorders, and nervous system diseases, and to evaluate the efficacy and safety of drugs targeting the IGF1 pathway.

Gene targeting strategy for B-hIGF1 mice. A chimeric CDS that encodes mouse Igf1 signal peptide and human IGF1 propeptide, followed by mouse 3’UTR-STOP is inserted right after mouse Igf1 gene to replace the exon 2 of mouse Igf1 gene. The chimeric IGF1 protein expression will be driven by endogenous mouse Igf1 promoter, while mouse Igf1 gene transcription and translation will be disrupted. 

Strain specific IGF1 expression analysis in homozygous B-hIGF1 mice by ELISA. Serum were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hIGF1 mice (H/H) (n=3, male, 6-week old), and analyzed by ELISA with species-specific IGF1 ELISA kit (mouse IGF1: R&D systems, MG100; human IGF1: R&D systems, DG100B). Mouse IGF1 was only detectable in wild-type C57BL/6JNifdc mice. Human IGF1 was exclusively detectable in homozygous mice but not in wild-type mice.