Chrdl1, also known as Chordin-like 1, is a secreted protein that serves as an endogenous antagonist of bone morphogenetic proteins (BMPs), especially BMP4 [1,3,4]. By interacting with BMP4, it is involved in multiple biological pathways and has overall importance in processes like cell differentiation, development, and tissue homeostasis. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, can be valuable in further elucidating its functions.

In glioma stem-like cells (GSCs), depletion of CHRDL1 using shRNA-mediated stable transduction decreased functional and molecular stemness traits and enhanced radiation sensitivity, suggesting CHRDL1 enforces stemness in GSCs [1]. In oral squamous cell carcinoma (OSCC), CHRDL1 inhibited metastasis by suppressing MED29 through the inhibition of the MAPK signaling pathway [2]. In the developing mouse retina, conditional overexpression of Chrdl1, which inhibits Bmp4, disrupted both neuronal and Müller glial differentiation and impaired visual function [3]. In myocardial infarction, Chrdl1 protected cardiomyocytes from death, induced autophagy, inhibited fibrosis, and maladaptive cardiac remodeling by binding and inhibiting extracellular BMP4 and TGF-β [4]. In colorectal cancer, CHRDL1 was downregulated, and its overexpression inhibited cell growth, migration, invasion, angiogenesis, and reversed epithelial-mesenchymal transformation through the TGF-β/VEGF pathway [5].

In conclusion, Chrdl1 is a key regulator in various biological processes and diseases. Its role as a BMP4 antagonist is crucial in maintaining cell fate decisions during development and in disease-related cell behaviors. The use of gene-targeted mouse models, such as KO or CKO, has provided significant insights into how Chrdl1 functions in glioma, OSCC, retinal development, myocardial infarction, and colorectal cancer, helping to understand disease mechanisms and potentially develop new therapeutic strategies.

References:

1. Berglar, Inka, Hehlgans, Stephanie, Wehle, Andrej, Kögel, Donat, Linder, Benedikt. 2022. CHRDL1 Regulates Stemness in Glioma Stem-like Cells. In Cells, 11, . doi:10.3390/cells11233917. https://pubmed.ncbi.nlm.nih.gov/36497175/

2. Huang, Songkai, Zhang, Junwei, Qiao, Yu, Liang, Jun, Ouyang, Kexiong. 2024. CHRDL1 inhibits OSCC metastasis via MAPK signaling-mediated inhibition of MED29. In Molecular medicine (Cambridge, Mass.), 30, 187. doi:10.1186/s10020-024-00956-y. https://pubmed.ncbi.nlm.nih.gov/39462350/

3. Liu, Dongmei, Pu, Zeyuan, Li, Baige, Xie, Ting, Shen, Yin. 2024. Chrdl1-mediated BMP4 inhibition disrupts the balance between retinal neurons and Müller Glia. In Cell death discovery, 10, 367. doi:10.1038/s41420-024-02129-6. https://pubmed.ncbi.nlm.nih.gov/39152126/

4. Ruozi, Giulia, Bortolotti, Francesca, Mura, Antonio, Zacchigna, Serena, Giacca, Mauro. 2022. Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library. In Science translational medicine, 14, eabo0699. doi:10.1126/scitranslmed.abo0699. https://pubmed.ncbi.nlm.nih.gov/36044596/

5. Li, Junfeng, Jiang, Zhongxiang, He, Jin, Xu, Shuman, Jiang, Zheng. 2024. Effect of CHRDL1 on angiogenesis and metastasis of colorectal cancer cells via TGF-β/VEGF pathway. In Molecular carcinogenesis, 63, 1092-1105. doi:10.1002/mc.23711. https://pubmed.ncbi.nlm.nih.gov/38415870/