Emilin1, or elastin-microfibril-interface-located-protein-1, is a structural component of the elastic fiber network, localizing to the interface between fibrillin microfibril scaffolds and the elastin core. It plays a crucial role in maintaining connective tissue integrity, and is involved in pathways such as elastogenesis, collagen fibrillogenesis, and growth factor signaling [1]. Gene knockout mouse models have been instrumental in uncovering its functions in vivo.

In Emilin1-deficient humans and mice, there are impairments in EFEMP2 extracellular matrix deposition and LOX activity, leading to impaired elastogenesis, reduced collagen cross-linking, and aberrant growth factor signaling. This results in phenotypes like arterial tortuosity, osteopenia, abnormal trabecular bone formation, and connective tissue disorders resembling autosomal-recessive cutis laxa type 1B [1]. In skin, Emilin1 deficiency causes dermal and epidermal hyperproliferation and accelerated wound closure, due to a lack of interaction with α4β1 and α9β1 integrins, which activates the PI3K/Akt and Erk1/2 pathways [2]. Emilin1-deficient mice also show structural and functional defects of the lymphatic vasculature, including hyperplasia, enlargement of lymphatic vessels, and lymphedema [3]. In tumor-related studies, an Emilin1-negative microenvironment promotes tumor cell proliferation, lymphangiogenesis, and lymph node invasion [4]. Abrogation of the Emilin1-β1 integrin interaction promotes experimental colitis and colon carcinogenesis, with higher tumor incidence and more severe colitis in mutant mice [5]. Additionally, Emilin1 knockout animals display increased blood pressure, as Emilin1 inhibits TGF-β signaling by preventing proTGF-β maturation [6].

In conclusion, Emilin1 is essential for maintaining the integrity of connective tissues, lymphatic vessels, and regulating blood pressure. Its role in inhibiting cell proliferation in normal tissues and its anti-tumor effects in the microenvironment are significant. The use of Emilin1 knockout mouse models has provided valuable insights into its functions in diseases related to connective tissue disorders, skin conditions, lymphatic system abnormalities, tumors, colitis, and hypertension.

References:

1. Adamo, Christin S, Beyens, Aude, Schiavinato, Alvise, Sengle, Gerhard, Callewaert, Bert. 2022. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis. In American journal of human genetics, 109, 2230-2252. doi:10.1016/j.ajhg.2022.10.010. https://pubmed.ncbi.nlm.nih.gov/36351433/

2. Danussi, Carla, Petrucco, Alessandra, Wassermann, Bruna, Colombatti, Alfonso, Spessotto, Paola. 2011. EMILIN1-α4/α9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation. In The Journal of cell biology, 195, 131-45. doi:10.1083/jcb.201008013. https://pubmed.ncbi.nlm.nih.gov/21949412/

3. Danussi, Carla, Spessotto, Paola, Petrucco, Alessandra, Bressan, Giorgio M, Colombatti, Alfonso. 2008. Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. In Molecular and cellular biology, 28, 4026-39. doi:10.1128/MCB.02062-07. https://pubmed.ncbi.nlm.nih.gov/18411305/

4. Danussi, Carla, Petrucco, Alessandra, Wassermann, Bruna, Colombatti, Alfonso, Spessotto, Paola. 2012. An EMILIN1-negative microenvironment promotes tumor cell proliferation and lymph node invasion. In Cancer prevention research (Philadelphia, Pa.), 5, 1131-43. doi:10.1158/1940-6207.CAPR-12-0076-T. https://pubmed.ncbi.nlm.nih.gov/22827975/

5. Capuano, Alessandra, Pivetta, Eliana, Sartori, Giulio, Mongiat, Maurizio, Spessotto, Paola. 2019. Abrogation of EMILIN1-β1 integrin interaction promotes experimental colitis and colon carcinogenesis. In Matrix biology : journal of the International Society for Matrix Biology, 83, 97-115. doi:10.1016/j.matbio.2019.08.006. https://pubmed.ncbi.nlm.nih.gov/31479698/

6. Zacchigna, Luca, Vecchione, Carmine, Notte, Antonella, Lembo, Giuseppe, Bressan, Giorgio M. . Emilin1 links TGF-beta maturation to blood pressure homeostasis. In Cell, 124, 929-42. doi:. https://pubmed.ncbi.nlm.nih.gov/16530041/