Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI11

Abstract

Disruptions of LGI1 in glioblastoma (GBM) cell lines and LGI1 mutations in families with autosomal dominant epilepsy imply a role for LGI1 in glial cells as well as in neurons. Although we and others could not find LGI1 mutations in malignant gliomas, our initial studies appeared to support the idea that LGI1 is poorly expressed or absent in these tumors. Microarray data suggested that LGI1 could be involved in the control of matrix metalloproteinases, and we found that tumors derived from U87 glioblastoma cells overexpressing LGI1 were less aggressive than U87 control tumors. To our surprise, we observed that LGI1 expression after differentiation of murine neural stem cells was robust in neurons but negligible in glial cells, in agreement with immunohistochemistry studies on rodent brain. This observation could suggest that the variable levels of LGI1 expression in gliomas reflect the presence of neurons entrapped within the tumor. To test this hypothesis, we investigated LGI1 expression in parallel with expression of the neuronal marker NEF3 by real-time PCR on 30 malignant gliomas. Results showed a strong, positive correlation between the expression levels of these two genes (P < 0.0001). Thus, our data confirm that LGI1 is involved in cell-matrix interactions but suggest that its expression is not relevant in glial cells, implying that its role as a tumor suppressor in gliomas should be reconsidered.

LGI1mutations in autosomal dominant and sporadic lateral temporal epilepsy

“…An alternative functional hypothesis postulates a role for LGI1 in brain development, as suggested by its expression in the developing mouse brain [Piepoli et al, 2006;Ribeiro et al, 2008] and by the structural homology of the LRR region with that of other LRR proteins essential for the development of the central nervous system, such as slit, tartan, and toll [Cowell, 2002]. This hypothesis has recently received support by in vitro experiments showing that LGI1 is involved in the control of proliferation and survival of neuroblastoma cell lines [Gabellini et al, 2006].…”

“…However, neither point mutations affecting the LGI1 coding sequence nor differential methylation of its core promoter region could be demonstrated in these tumors, arguing against a role of LGI1 as a tumor suppressor gene [Krex et al, 2002;Piepoli et al, 2006;Somerville et al, 2000]. Recent studies have implicated LGI1 in the control of proliferation and invasiveness of glioma cell lines [Kunapuli et al, 2003].…”

“…LGI1 expression in the brain is predominantly neuronal, with little or no expression found in glial cells [Kalachikov et al, 2002;Piepoli et al, 2006;Senechal et al, 2005]. In situ hybridization experiments have shown that expression of the murine Lgi1 gene is higher in some areas, particularly in the neocortex and limbic regions [Kalachikov et al, 2002;Senechal et al, 2005].…”

Distribution of the epilepsy-related Lgi1 protein in rat cortical neurons

“…Previous low-resolution immunohistochemical studies Piepoli et al 2006) showed the presence of the Lgi1 protein in neurons, but little information could be soma (a, b), Lgi1 molecules occurs on rough endoplasmic reticulum (arrows), on Golgi complexes (G) and free in the cytoplasm (thin arrows), while in axons (c) they appear to be preferentially associated with neurotubules and neuroWlaments (arrowheads). No signal is present at synapses (asterisk).…”

“…In low-resolution immunohistochemical studies Piepoli et al 2006), the Lgi1 protein was found to be predominantly expressed in neurons. Schulte et al (2006) provided evidence that the Lgi1 protein is associated with the presynaptic, rapidly inactivating Kv1 potassium channel suggesting its involvement in the control of inactivation of this channel; Fukata et al (2006) showed that Lgi1 selectively binds to ADAM22, a postsynaptic membrane receptor protein, thereby potentiating synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid currents in hippocampal slices.…”