Smad5, short for small mothers against decapentaplegic 5, is a receptor-regulated member of the Smad family proteins. It mainly functions in its phosphorylated form within the bone morphogenetic protein (BMP) signaling pathway, which is crucial for embryonic development and adult homeostasis [1,2,5]. Genetic models, such as KO/CKO mouse models, are valuable tools for studying its gene function [6].

In mice, deletion of SMAD1/5 using progesterone receptor (PR)-cre led to endometrial defects, including cystic endometrial glands, hyperproliferative endometrial epithelium during the implantation window, and impaired apicobasal transformation, resulting in infertility. This shows that SMAD1/5 is required for endometrial receptivity and embryo implantation through the uterine BMP signaling pathway [3]. In pulmonary arterial hypertension (PAH) patients, two SMAD5 variants were found. Expression of one variant in pulmonary artery smooth muscle cells (PASMCs) increased cell viability via higher proliferation, while the other led to lower cell viability due to increased apoptosis, suggesting SMAD5 as a potential novel PAH gene [4].

In conclusion, Smad5 is essential in the BMP signaling pathway, playing significant roles in endometrial receptivity, embryo implantation, and potentially in the pathogenesis of pulmonary arterial hypertension. Mouse models have been instrumental in revealing these functions, contributing to our understanding of related biological processes and disease mechanisms.

References:

1. Lin, Zeqiang, Zhuang, Jiayu, He, Lixia, Lu, Wenju, Zhang, Zili. 2024. Exploring Smad5: a review to pave the way for a deeper understanding of the pathobiology of common respiratory diseases. In Molecular medicine (Cambridge, Mass.), 30, 225. doi:10.1186/s10020-024-00961-1. https://pubmed.ncbi.nlm.nih.gov/39578779/

2. Liu, Bing, Mao, Ning. . Smad5: signaling roles in hematopoiesis and osteogenesis. In The international journal of biochemistry & cell biology, 36, 766-70. doi:. https://pubmed.ncbi.nlm.nih.gov/15061132/

3. Monsivais, Diana, Nagashima, Takashi, Prunskaite-Hyyryläinen, Renata, Lee, Se-Jin, Matzuk, Martin M. 2021. Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis. In Nature communications, 12, 3386. doi:10.1038/s41467-021-23571-5. https://pubmed.ncbi.nlm.nih.gov/34099644/

4. Cao, Ding, Grünig, Ekkehard, Sirenko, Yuriy, Laugsch, Magdalena, Eichstaedt, Christina A. . SMAD5 as a novel gene for familial pulmonary arterial hypertension. In Clinical science (London, England : 1979), 139, 15-27. doi:10.1042/CS20241340. https://pubmed.ncbi.nlm.nih.gov/39631055/

5. Orlowski, John. 2017. SMAD5 signaling: more than meets the nuclei. In Cell research, 27, 1075-1076. doi:10.1038/cr.2017.101. https://pubmed.ncbi.nlm.nih.gov/28809394/

6. Liao, Zian, Tang, Suni, Nozawa, Kaori, Monsivais, Diana, Matzuk, Martin. 2024. Affinity-tagged SMAD1 and SMAD5 mouse lines reveal transcriptional reprogramming mechanisms during early pregnancy. In eLife, 12, . doi:10.7554/eLife.91434. https://pubmed.ncbi.nlm.nih.gov/38536963/