Alternative titles; symbols
HGNC Approved Gene Symbol: LLGL1
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:18,225,635-18,244,875 (from NCBI)
Strand et al. (1995) stated that in Drosophila more than 50 tumor suppressor genes have been identified by mutations causing tissue overgrowth during development (see 600723). Recessive mutations in these genes interrupt the differentiation of primordial cells and result in excessive cell proliferation. These malignancies occur in either the presumptive adult optic centers of the larval brain, the imaginal discs, or the hematopoietic organs. The development of the mutant animals is arrested and they die as larvae or pseudopupae. Inactivation of the tumor suppressor gene 'lethal(2) giant larvae' (D-lgl) of Drosophila leads to malignant transformation of the presumptive adult optic centers in the larval brain and tumors of the imaginal discs. These malignancies result from the disorganization of a cytoskeletal network in which the D-LGL protein participates. Strand et al. (1995) described the isolation of a cDNA encoding the human homolog of the D-LGL gene, which they designated HUGL. In Northern blots the cDNA recognized a 4.5-kb RNA transcript. The HUGL gene (also symbolized LLGL) is expressed in brain, kidney, and muscle but is barely seen in heart and placenta. The HUGL cDNA has a long open reading frame with the potential to encode a protein of 1,057 amino acids with a predicted molecular weight of 115 kD. To further substantiate and identify the HUGL protein, Strand et al. (1995) prepared polyclonal rabbit antibodies against synthetic peptides corresponding to the N and C termini of the predicted translation product of the HUGL gene. The affinity-purified anti-HUGL antibodies recognized a single protein with an apparent molecular weight of approximately 115 kD. Similar to the Drosophila protein, HUGL is part of a cytoskeletal network and is associated with nonmuscle myosin II heavy chain (type A, 160775; type B, 160776) and a kinase that specifically phosphorylates HUGL at serine residues.
Koyama et al. (1996) isolated cDNA clones from a human brain cDNA library for the human homolog of the murine Llglh gene that was originally isolated as a homolog of the Drosophila tumor suppressor gene 'lethal(2) giant larvae' (l(2)gl). The full-length cDNA encodes 1,033 amino acids with 40% identity to the Drosophila l(2)gl amino acid sequence and 86% identity to the murine homolog. Northern analysis of mRNA revealed that this gene was expressed as a 4.4-kb transcript in a wide range of tissues; however, more abundant expression occurred in brain and testes.
Ohshiro et al. (2000) demonstrated in Drosophila that lethal giant larvae (Lgl) is essential for asymmetric cortical localization of all basal determinants in mitotic neuroblasts, and is therefore indispensable for neural fate decisions. Lgl, which itself is uniformly cortical, interacts with several types of myosin to localize the determinants. Another tumor suppressor protein, lethal discs large (Dlg) (DLG1; 601014), participates in this process by regulating the localization of Lgl. The localization of the apical components is unaffected in Lgl or Dlg mutants. Thus, Lgl and Dlg act in a common process that differentially mediates cortical protein targeting in mitotic neuroblasts, and creates intrinsic differences between daughter cells.
Peng et al. (2000) showed that the tumor suppressor genes Lgl and Dlg regulate basal protein targeting, but not apical complex formation or spindle orientation, in both embryonic and larval Drosophila neuroblasts. Dlg protein is apically enriched and is required for maintaining cortical localization of Lgl protein. Basal protein targeting requires microfilament and myosin function, yet the Lgl phenotype is strongly suppressed by reducing levels of myosin II. Peng et al. (2000) concluded that Dlg and Lgl promote, and myosin II inhibits, actomyosin-dependent basal protein targeting in neuroblasts.
Zarnescu et al. (2005) found that mouse Lgl was expressed at low levels in the cytoplasm along with Fmr1 (309550). Overexpression of fluorescence-tagged Fmr1 directed the assembly of endogenous Lgl into perinuclear and cytoplasmic granules. In a mouse catecholaminergic cell line, Fmr1 overexpression resulted in reorganization of endogenous Lgl into Fmr1-containing granules in the perinuclear region and within developing neurites.
Dollar et al. (2005) demonstrated that a vertebrate homolog of Lgl associates with dishevelled (601365), an essential mediator of Wnt signaling, and that dishevelled regulates the localization of Lgl in Xenopus ectoderm and Drosophila follicular epithelium. Dollar et al. (2005) showed that both Lgl and dishevelled are required for normal apical-basal polarity of Xenopus ectodermal cells. In addition, Dollar et al. (2005) showed that the Wnt receptor frizzled 8 (606146), but not frizzled 7 (603410), causes Lgl to dissociate from the cortex with the concomitant loss of its activity in vivo. Dollar et al. (2005) concluded that their findings suggest a molecular basis for the regulation of cell polarity by frizzled and dishevelled.
By Southern blot analysis of DNA from rodent/human somatic cell hybrids and by fluorescence in situ hybridization, Strand et al. (1995) determined that the HUGL locus spans at least 25 kb on chromosome 17p12-p11.2 centromeric to the p53 gene (191170).
By fluorescence in situ hybridization, Koyama et al. (1996) localized the human gene to 17p11.2. They reported that in patients with Smith-Magenis syndrome (182290) with microdeletions of chromosome 17p11.2, hybridization occurred only on one chromosome 17, i.e., on the normal chromosome.
Campbell et al. (1997) reported that the LLGL1 gene is adjacent to FLII (600362), and that the 3-prime ends of the 2 transcripts overlap. The overlap region contains poly(A) signals for both genes and is highly conserved between human and mouse.
Klezovitch et al. (2004) found that loss of Lgl1 in mice resulted in formation of neuroepithelial rosette-like structures, similar to the neuroblastic rosettes in human primitive neuroectodermal tumors. Newborn Lgl1 -/- pups developed severe hydrocephalus and died neonatally. A large proportion of Lgl1 -/- neural progenitor cells failed to exit the cell cycle and differentiate, and instead continued to proliferate and died by apoptosis. Dividing Lgl1 -/- cells were unable to asymmetrically localize the Notch inhibitor Numb (603728), and the resulting failure of asymmetric cell divisions may have been responsible for the hyperproliferation and lack of differentiation.
Lee et al. (2006) tested whether cell polarity genes, known to regulate embryonic neuroblast asymmetric cell division, also regulate neuroblast self-renewal. Clonal analysis in Drosophila larval brains showed that pins (see 609245) mutant neuroblasts rapidly fail to self-renew, whereas lgl mutant neuroblasts generate multiple neuroblasts. Notably, lgl pins double mutant neuroblasts all divide symmetrically to self-renew, filling the brain with neuroblasts at the expense of neurons. The lgl pins neuroblasts show ectopic cortical localization of atypical protein kinase C (aPKC; see 176960), and a decrease in aPKC expression reduces neuroblast numbers, suggesting that aPKC promotes neuroblast self-renewal. In support of this hypothesis, Lee et al. (2006) found that neuroblast-specific overexpression of membrane-targeted aPKC, but not a kinase-dead version, induced ectopic neuroblast self-renewal. Lee et al. (2006) concluded that cortical aPKC kinase activity is a potent inducer of neuroblast self-renewal.
Campbell, H. D., Fountain, S., Young, I. G., Claudianos, C., Hoheisel, J. D., Chen, K.-S., Lupski, J. R. Genomic structure, evolution, and expression of human FLII, a gelsolin and leucine-rich-repeat family member: overlap with LLGL. Genomics 42: 46-54, 1997. [PubMed: 9177775] [Full Text: https://doi.org/10.1006/geno.1997.4709]
Dollar, G. L., Weber, U., Mlodzik, M., Sokol, S. Y. Regulation of lethal giant larvae by Dishevelled. Nature 437: 1376-1380, 2005. [PubMed: 16251968] [Full Text: https://doi.org/10.1038/nature04116]
Klezovitch, O., Fernandez, T. E., Tapscott, S. J., Vasioukhin, V. Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Genes Dev. 18: 559-571, 2004. [PubMed: 15037549] [Full Text: https://doi.org/10.1101/gad.1178004]
Koyama, K., Fukushima, Y., Inazawa, J., Tomotsune, D., Takahashi, N., Nakamura, Y. The human homologue of the murine Llglh gene (LLGL) maps within the Smith-Magenis syndrome region in 17p11.2. Cytogenet. Cell Genet. 72: 78-82, 1996. [PubMed: 8565641] [Full Text: https://doi.org/10.1159/000134167]
Lee, C.-Y., Robinson, K. J., Doe, C. Q. Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation. Nature 439: 594-598, 2006. [PubMed: 16357871] [Full Text: https://doi.org/10.1038/nature04299]
Ohshiro, T., Yagami, T., Zhang, C., Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408: 593-596, 2000. [PubMed: 11117747] [Full Text: https://doi.org/10.1038/35046087]
Peng, C.-Y., Manning, L., Albertson, R., Doe, C. Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408: 596-600, 2000. [PubMed: 11117748] [Full Text: https://doi.org/10.1038/35046094]
Strand, D., Unger, S., Corvi, R., Hartenstein, K., Schenkel, H., Kalmes, A., Merdes, G., Neumann, B., Krieg-Schneider, F., Coy, J. F., Poustka, A., Schwab, M., Mechler B. M. A human homologue of the Drosophila tumour suppressor gene l(2)gl maps to 17p11.2-12 and codes for a cytoskeletal protein that associates with nonmuscle myosin II heavy chain. Oncogene 11: 291-301, 1995. [PubMed: 7542763]
Zarnescu, D. C., Jin, P., Betschinger, J., Nakamoto, M., Wang, Y., Dockendorff, T. C., Feng, Y., Jongens, T. A., Sisson, J. C., Knoblich, J. A., Warren, S. T., Moses, K. Fragile X protein functions with lgl and the PAR complex in flies and mice. Dev. Cell 8: 43-52, 2005. [PubMed: 15621528] [Full Text: https://doi.org/10.1016/j.devcel.2004.10.020]