• TFR1 is a membrane protein essential for iron transport and metabolism, expressed across diverse human tissues. It is markedly upregulated in many cancers, where targeting TFR1 can suppress tumor growth and metastasis. Beyond oncology, TFR1 is also implicated in anemia, neurodegenerative disorders, and other conditions.
• Because TFR1 is highly expressed on brain endothelial cells, it can be leveraged for receptor-mediated transcytosis (RMT), enabling efficient transport of large molecules across the BBB and making it an attractive target for CNS drug delivery.
• PMP22 is predominantly expressed in the compact myelin of the peripheral nervous system, and its level requires strict regulation. Gene mutations lead to changes in the protein level, causing more than 50% of inherited peripheral neuropathies, such as CMT1A, HNPP, and CMT1E. Gene overexpression and point mutations result in gain-of-function phenotypes, while gene deletion leads to loss-of-function phenotypes.

Gene targeting strategy for B-Tg(hPMP22)/hTFR1 mice.

The exons 4-19 of mouse Tfr1 gene that encode extracellular domain are replaced by human counterparts in B-hTFR1 mice. The genomic region of mouse Tfr1 gene that encodes cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The chimeric TFR1 expression is driven by endogenous mouse Tfr1 promoter, while mouse Tfr1 gene transcription and translation will be disrupted.

The BAC containing the whole human PMP22 genome sequence was randomly inserted into mouse genome in B-Tg(hPMP22) mice.

B-Tg(hPMP22)/hTFR1 mice were ontained by crossing B-Tg(hPMP22) mice (113146) and B-hTFR1 mice (110861).

Behavioral performance in wild-type C57BL/6JNifdc and B-Tg(hPMP22)/hTFR1 mice.

Clasping tests were conducted to assay the behavioral performance in wild-type C57BL/6JNifdc (4-month-old, n=10) and B-Tg(hPMP22)/hTFR1  mice (4-month-old, n=10). A, female. B, male.

B-Tg(hPMP22)/hTFR1 mice show significantly higher neuroscores versus wild-type mice, suggesting impaired neurological function. Values are expressed as mean ± SEM. Significance was determined by unpaired t-test, *P < 0.05, **P < 0.01, ***P < 0.001.

Behavioral performance in wild-type C57BL/6JNifdc and B-Tg(hPMP22)/hTFR1 mice. Rotarod tests were conducted to assay the behavioral performance in wild-type C57BL/6JNifdc and B-Tg(hPMP22)/hTFR1 mice (4-month-old， n=10). A, female. B, male. B-Tg(hPMP22)/hTFR1 mice showed decreased fall latency, glide speed and total distance, showing motor dysfunction at 4 months of age. Values are expressed as mean ± SEM. Significance was determined by unpaired t-test.  *P < 0.05, **P < 0.01, ***P < 0.001.