Nrarp, short for Notch-regulated ankyrin repeat protein, is a key gene that acts as a molecular link between the Notch and Wnt signaling pathways [3,4,8]. It contains two ankyrin repeats and its expression is transcriptionally regulated by the Notch signaling pathway [7]. Nrarp plays significant roles in multiple biological processes such as cell fate determination during embryogenesis, neural-crest-cell differentiation, osteoblastogenesis, and angiogenesis [4,5,6,8].

In T-cell acute lymphoblastic leukemia (T-ALL), Nrarp shows a dual role. Overexpression of Nrarp can block NOTCH1 signaling and delay the proliferation of T-ALL cells with high Notch1 signaling, but promote the expansion of those with lower Notch1 activity. It interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low Notch levels [1]. In reninoma, structural variants lead to the removal of NRARP while generating canonical activating rearrangements of NOTCH1, indicating dysregulated Notch pathway signalling [2]. In breast cancer cells, downregulation of NRARP exerts anti-tumor activities through Wnt/β-catenin-mediated signals, and miR-130a-3p can inhibit NRARP expression to achieve this [3]. In zebrafish, knockdown of Nrarp-a affects Wnt-signalling-dependent neural-crest-cell development by regulating LEF1 protein stability [4]. In osteoblasts, miR-487b-3p impairs osteoblastogenesis by targeting Nrarp, which in turn suppresses Runx-2 and Wnt signaling [6]. In angiogenesis, loss of Nrarp, Lef1, or endothelial Ctnnb1 causes vessel regression as Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density [8].

In conclusion, Nrarp is crucial in coordinating Notch and Wnt signaling pathways across different biological processes. Its study through gene knockdown or knockout models in organisms like mice and zebrafish has revealed its significance in diseases such as T-ALL, reninoma, and breast cancer, as well as in normal developmental processes like neural-crest-cell differentiation, osteoblastogenesis, and angiogenesis.

References:

1. Pinto, Inês, Duque, Mafalda, Gonçalves, Joana, Barata, João T, Fragoso, Rita. 2019. NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling. In Oncogene, 39, 975-986. doi:10.1038/s41388-019-1042-9. https://pubmed.ncbi.nlm.nih.gov/31586130/

2. Treger, Taryn D, Lawrence, John E G, Anderson, Nathaniel D, Behjati, Sam, Chowdhury, Tanzina. 2023. Targetable NOTCH1 rearrangements in reninoma. In Nature communications, 14, 5826. doi:10.1038/s41467-023-41118-8. https://pubmed.ncbi.nlm.nih.gov/37749094/

3. Poodineh, Jafar, Sirati-Sabet, Majid, Rajabibazl, Masoumeh, Ghasemian, Majid, Mohammadi-Yeganeh, Samira. 2022. Downregulation of NRARP exerts anti-tumor activities in the breast tumor cells depending on Wnt/β-catenin-mediated signals: The role of miR-130a-3p. In Chemical biology & drug design, 100, 334-345. doi:10.1111/cbdd.14113. https://pubmed.ncbi.nlm.nih.gov/35797350/

4. Ishitani, Tohru, Matsumoto, Kunihiro, Chitnis, Ajay B, Itoh, Motoyuki. . Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability. In Nature cell biology, 7, 1106-12. doi:. https://pubmed.ncbi.nlm.nih.gov/16228014/

5. Lamar, E, Deblandre, G, Wettstein, D, Niehrs, C, Kintner, C. . Nrarp is a novel intracellular component of the Notch signaling pathway. In Genes & development, 15, 1885-99. doi:. https://pubmed.ncbi.nlm.nih.gov/11485984/

6. John, Aijaz A, Prakash, Ravi, Singh, Divya. . miR-487b-3p impairs osteoblastogenesis by targeting Notch-regulated ankyrin-repeat protein (Nrarp). In The Journal of endocrinology, 241, 249-263. doi:10.1530/JOE-19-0015. https://pubmed.ncbi.nlm.nih.gov/30978699/

7. Krebs, L T, Deftos, M L, Bevan, M J, Gridley, T. . The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway. In Developmental biology, 238, 110-9. doi:. https://pubmed.ncbi.nlm.nih.gov/11783997/

8. Phng, Li-Kun, Potente, Michael, Leslie, Jonathan D, Thurston, Gavin, Gerhardt, Holger. . Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. In Developmental cell, 16, 70-82. doi:10.1016/j.devcel.2008.12.009. https://pubmed.ncbi.nlm.nih.gov/19154719/