Developmental analysis of Lingo‐1/Lern1 protein expression in the mouse brain: Interaction of its intracellular domain with Myt1l

Abstract

Lingo-1 (also known as Lern1) is a component of the Nogo receptor complex that mediates intracellular signaling in response to myelin associated inhibitors (MAIs): NogoA, MAG, and Omgp. Signaling through Nogo receptor extends to more than its well known role in preventing axon regeneration after lesion in the CNS, being implicated in neuronal functional maturation. Using Lingo-1-deficient mice, it has been demonstrated that Lingo-1 plays relevant roles in oligodendrocyte differentiation during brain development, and that treatment with Lingo-1 antagonists can improve axon regeneration after lesion in adult mice by decreasing MAI mediated signaling. However, a detailed description of the pattern of expression of Lingo-1 protein in correlation with the other partners of Nogo receptor is missing. Here, we show that components of the Nogo receptor complex, Lingo-1, NgR1, p75, and TROY coexist in mouse brain in a defined time window only at later postnatal stages. We have also determined the Lingo-1 distribution showing expression in particular subsets of neurons, but not in myelinating mature oligodendrocytes. Surprisingly, Lingo-1 is expressed at early developmental stages without NgR1, which supports the notion that Lingo-1 may participate in other activities in developing neurons different from oligodendrocyte maturation or axon extension inhibition in the adult. Finally, we propose that the intracellular domain of Lingo-1 contributes to signaling and show that it interacts with the postmitotic neuronal specific zinc finger protein Myt1l, suggesting that Lingo-1 may regulate Myt1l transcription factor activity by affecting its subcellular localization.

The brain-specific Neural Zinc Finger transcription factor 2b (NZF-2b/7ZFMyt1) causes suppression of cocaine-induced locomotor activity

“…In addition, NZF-2b/7ZFMyt1 interacts with Lingo1 (Llorens et al, 2008), a component of the Nogo receptor complex that mediates intracellular signaling in response to myelinassociated inhibitors (MAIs). This interaction is responsible for the intracellular localization and regulation of transcriptional activity of NZF-2b/7ZFMyt1, whereby Lingo1 causes cytoplasmic localization of NZF-2b/7ZFMyt1 (Llorens et al, 2008) and transcriptional inactivation. Interestingly BDNF induces expression of Lingo 1 (Trifunovski et al, 2004).…”

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders

“…Myt1l has been reported to directly interact with the intracellular domain of Lingo-1, suggesting that Lingo-1 may regulate Myt1l transcription factor activity by affecting its subcellular localization (Llorens et al, 2008). It is thought that this may occur in two different ways: firstly Lingo-1 may interact with Myt1l to regulate its transcription factor activity by retaining it in the cytoplasm; or secondly, Lingo-1 may transduce intracellular signals by docking additional Myt1l cofactors or modifying enzymes (Llorens et al, 2008).…”

“…It is thought that this may occur in two different ways: firstly Lingo-1 may interact with Myt1l to regulate its transcription factor activity by retaining it in the cytoplasm; or secondly, Lingo-1 may transduce intracellular signals by docking additional Myt1l cofactors or modifying enzymes (Llorens et al, 2008). Myt1 and Myt1l display a high degree of identity, and therefore are highly likely to share the same binding sites, considering the ability of the Myt1l protein to bind the oligonucleotide sequence containing the proteolipid protein site that was originally intended to clone Myt1.…”

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats

“…Altogether, the activation of this trimolecular receptor complex sets up a signaling cascade leading to growth cone collapse, preventing further axonal growth and inhibiting myelination 18,24 . Additional signaling co-factors such as With No Lysine K (WNK1) 25 , Myelin transcription factor 1 (Myt1) and its homolog Myt1-like (Myt1l) are known to be associated with Lingo-1 signaling due to a lack of p75 and TROY receptors on Lingo-1 expressing neurons 26,27 . Genetic associations with schizophrenia have been previously reported for the Myt1l gene in different populations 28,29 , and the knockdown of Myt1 has been shown to induce apoptosis 30 , strengthening the relevance of studying this Lingo-1 cofactor in a neurodevelopmental PCP induced model for schizophrenia.…”