Bioscience Reports (2010) 30, 267-275 - C.-F. Chou and M. Ozaki

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Bioscience Reports (2010) 30, (267–275) (Printed in Great Britain)

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Original Paper

In silico analysis of neuregulin 1 evolution in vertebrates

Chih‑Fong Chou*¹ and Miwako Ozaki*†¹

*Laboratory for Neural Disorders, Waseda Singapore Institute for Biomedical Engineering, Waseda University, 11 Biopolis Way, Helios 05-01/02, Singapore 138667, Singapore, and †Institute for Biomedical Engineering, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku-ku, Tokyo 162-0041, Japan

Key words: isoform, myelination, neuregulin (NRG), nuclear localization signal (NLS), schizophrenia, synaptic transmission.

Abbreviations used: BACE1, β-site amyloid precursor protein-cleaving enzyme 1; CDS, coding sequence; EGF, epidermal growth factor; EQ, encephalization quotient; GGF2, glial growth factor-2; N-CDS, N-terminal CDS; NLS, nuclear localization signal; PKC, protein kinase C; RefSeq, Reference Sequence; RT–PCR, reverse transcription–PCR; NRG, neuregulin; sNRG1, soluble NRG1, TACE, TNFα (tumour necrosis factor α)-converting enzyme; TM, transmembrane; Vn protein, Vein protein.

¹Correspondence may be addressed to either of these authors (email chouchihfong@yahoo.com or mozaki@waseda.jp).

NRG1 (neuregulin 1) belongs to the NRG family of EGF (epidermal growth factor)-like signalling molecules involved in cell–cell communication during development and disease. It plays important roles in the developing tissues of the nerves, heart and mammary glands. Particularly in neurobiology, NRG1 signalling is associated with synaptic transmission, myelination of Schwann cells and the human disease of schizophrenia. Many different isoforms of NRG1 make the molecule highly sophisticated in biological activities and a great diversity of in vivo functions. The nervous system is a common trait in all bilateria (higher animals), but based on the BLAST information from the currently available databases it appears that NRG1 orthologues can only be identified in vertebrates. The gene was analysed in silico for type I–IV CDSs (coding sequences) from ten vertebrate genomes. The gene loci, structures of coding-intronic sequences, ClustalW program analyses, phylogenetic trees and conserved motifs in ecto- and cyto-plasmic domains were analysed and compared. Here, we conclude that non-mammalian vertebrates mainly carry type I (may have evolved a spacer different from mammalian isoforms), II and III NRG1s. The type IV NRG1 N-terminal CDSs can be identified from most of the mammalian genomes studied; however, the corresponding rodent sequences lack the start codon. The evolutionary conservation of a CDS⁵⁹-CDS²⁴-CDS¹⁰³ domain, intracellular phosphorylation sites and bipartite nuclear localization signals is of physiological significance.