Alternative titles; symbols
HGNC Approved Gene Symbol: LRRN1
Cytogenetic location: 3p26.2 Genomic coordinates (GRCh38): 3:3,799,431-3,849,834 (from NCBI)
LRRN1 regulates differentiation of embryonic stem cells by posttranslational modification of pluripotency factors (Liao et al., 2018).
Taguchi et al. (1996) cloned mouse Lrrn1, which they called Nlrr1. Nlrr1 is a predicted 716-amino acid transmembrane protein that contains an N-terminal signal peptide and 12 tandem leucine-rich repeat (LLR) motifs. Northern blot analysis and in situ hybridization showed that Nlrr1 was expressed primarily in mouse central nervous system (CNS), with expression also detected in embryonic cartilage.
Using in situ hybridization analysis of chick embryos, Tossell et al. (2011) showed that Lrrn1 was expressed in neural plate from Hamburger Hamilton stage-5 (HH5), with strong expression throughout neural plate at HH8, when neural folds have formed. From HH9, Lrrn1 was downregulated in the midbrain-hindbrain boundary (MHB) region, but high expression remained both anteriorly and posteriorly in neural tube. Downregulation became increasingly marked as development proceeded, and at HH11, Lrrn1 was absent in the posterior midbrain vesicle and anterior hindbrain.
Using confocal microscopy and immunostaining, Liao et al. (2018) showed that LRRN1 localized at the surface of undifferentiated human embryonic stem cells (hESCs).
Gross (2021) mapped the LRRN1 gene to chromosome 3p26.2 based on an alignment of the LRRN1 sequence (GenBank BC034947) with the genomic sequence (GRCh38).
Tossell et al. (2011) found that Lrrn1 expression was downregulated by Fgf8 (600483) at the midbrain-hindbrain boundary (MHB) in chick embryos, thereby creating a differential affinity between midbrain and hindbrain compartments. Lrrn1 was required for formation of the MHB and organizer gene expression, as loss of Lrrn1 resulted in loss of morphologic constriction at the MHB and loss of Fgf8. Ectopic expression of Lrrn1 across the MHB caused loss of restriction of MHB gene expression borders and a shift in the morphologic boundary. Lrrn1 also regulated Lfng (602576), a glycosyltransferase that modulates Notch (see 190198) signaling, to maintain its expression in midbrain cells, which was instrumental in MHB boundary formation.
Using glycoproteomics, Liao et al. (2018) identified LRRN1 as a highly expressed protein in hESCs before differentiation into embryoid bodies (EBs). Knockdown of LRRN1 led to decreased proliferation of hESCs, likely due to increased apoptosis, and skewing of hESC differentiation toward endoderm and mesoderm lineages. Knockdown of LRRN1 in hESCs did not influence mRNA levels of the pluripotency factors OCT4 (POU5F1; 164177), NANOG (607937), and SOX2 (184429). Instead, regulation of these factors by LRRN1 occurred at the posttranslational level, as knockdown of LRRN1 led to export of these factors from nucleus to cytoplasm and suppressed their protein levels by activating proteasomal degradation. Further analysis indicated that LRRN1 knockdown decreased AKT (164730) phosphorylation, causing translocation of pluripotency factors and their degradation.
Gross, M. B. Personal Communication. Baltimore, Md. 11/16/2021.
Liao, C.-H., Wang, Y.-H., Chang, W.-W., Yang, B.-C., Wu, T.-J., Liu, W.-L., Yu, A. L., Yu, J. Leucine-rich repeat neuronal protein 1 regulates differentiation of embryonic stem cells by post-translational modifications of pluripotency factors. Stem Cells 36: 1514-1524, 2018. [PubMed: 29893054] [Full Text: https://doi.org/10.1002/stem.2862]
Taguchi, A., Wanaka, A., Mori, T., Matsumoto, K., Imai, Y., Tagaki, T., Tohyama, M. Molecular cloning of novel leucine-rich repeat proteins and their expression in the developing mouse nervous system. Molec. Brain Res. 35: 31-40, 1996. [PubMed: 8717337] [Full Text: https://doi.org/10.1016/0169-328x(95)00178-u]
Tossell, K., Andreae, L. C., Cudmore, C., Lang, E., Muthukrishnan, U., Lumsden, A., Gilthorpe, J. D., Irving, C. Lrrn1 is required for formation of the midbrain-hindbrain boundary and organiser through regulation of affinity differences between midbrain and hindbrain cells in chick. Dev. Biol. 352: 341-352, 2011. [PubMed: 21315708] [Full Text: https://doi.org/10.1016/j.ydbio.2011.02.002]