Larp1-KO Mouse

Larp1, short for La-related protein 1, is an RNA-binding protein belonging to the LARP superfamily. It is a key player in regulating the translation and stability of mRNAs, especially those containing a 5' terminal oligopyrimidine (5'TOP) motif. These TOP mRNAs encode ribosomal proteins and translation factors, and Larp1's activity is regulated by the mammalian target of rapamycin complex 1 (mTORC1) pathway. Larp1 is involved in crucial biological processes such as gametogenesis, embryogenesis, and cell division in animals, as well as stress acclimation in yeasts and plants [1,2].

In humans, evidence from a case series of seven probands with de novo heterozygous loss-of-function or missense variants in LARP1 showed that Larp1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder. Lower cellular levels of Larp1 protein in lymphocytes from an index proband led to reduced rates of aerobic respiration and glycolysis, suggesting that Larp1 contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain [3]. In hepatoblastoma (HB), Larp1 was found to be upregulated, and its knockdown abolished cell proliferation and triggered apoptosis, while overexpression incited HB progression. Mechanistically, O-GlcNAcylation of Larp1 by O-GlcNAc transferase protected it from degradation, and Larp1 then stabilized DKK4 mRNA, facilitating β-catenin protein expression and nuclear import [4].

In conclusion, Larp1 is a versatile mRNA-binding protein with essential functions in regulating mRNA translation and stability. Studies on Larp1, especially through loss-of-function models like those in humans, have revealed its significance in neurodevelopmental disorders and cancer, providing insights into the underlying molecular mechanisms and potential therapeutic targets for these diseases.

References:

1. Fonseca, Bruno D, Lahr, Roni M, Damgaard, Christian K, Alain, Tommy, Berman, Andrea J. 2018. LARP1 on TOP of ribosome production. In Wiley interdisciplinary reviews. RNA, 9, e1480. doi:10.1002/wrna.1480. https://pubmed.ncbi.nlm.nih.gov/29722158/

2. Deragon, Jean-Marc, Bousquet-Antonelli, Cécile. 2015. The role of LARP1 in translation and beyond. In Wiley interdisciplinary reviews. RNA, 6, 399-417. doi:10.1002/wrna.1282. https://pubmed.ncbi.nlm.nih.gov/25892282/

3. Chettle, James, Louie, Raymond J, Larner, Olivia, Sanders, Stephan J, Blagden, Sarah P. 2024. LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder. In HGG advances, 5, 100345. doi:10.1016/j.xhgg.2024.100345. https://pubmed.ncbi.nlm.nih.gov/39182167/

4. Cui, Zhongqi, He, Jiangtu, Zhu, Jiabei, Huang, Nan, Ma, Ji. . O-GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/β-catenin signalling. In Clinical and translational medicine, 13, e1239. doi:10.1002/ctm2.1239. https://pubmed.ncbi.nlm.nih.gov/37070251/