title: Structure-function analysis of Nel, a thrombospondin-1-like glycoprotein involved in neural development and functions.
abstract: Nel (neural epidermal growth factor (EGF)-like molecule) is a multimeric, multimodular extracellular glycoprotein with heparin-binding activity and structural similarities to thrombospondin-1. Nel is predominantly expressed in the nervous system and has been implicated in neuronal proliferation and differentiation, retinal axon guidance, synaptic functions, and spatial learning. The Nel protein contains an N-terminal thrombospondin-1 (TSP-N) domain, five cysteine-rich domains, and six EGF-like domains. However, little is known about the functions of specific domains of the Nel protein. In this study, we have performed structure-function analysis of Nel, by using a series of expression constructs for different regions of the Nel protein. Our studies demonstrate that the TSP-N domain is responsible for homo-multimer formation of Nel and its heparin-binding activity. In vivo, Nel and related Nell1 are expressed in several regions of the mouse central nervous system with partly overlapping patterns. When they are expressed in the same cells in vitro, Nel and Nell1 can form hetero-multimers through the TSP-N domain, but they do not hetero-oligomerize with thrombospondin-1. Whereas both the TSP-N domain and cysteine-rich domains can bind to retinal axons in vivo, only the latter causes growth cone collapse in cultured retinal axons, suggesting that cysteine-rich domains interact with and activate an inhibitory axon guidance receptor. These results suggest that Nel interacts with a range of molecules through its different domains and exerts distinct functions.
authors.affiliation: Aberdeen Developmental Biology Group, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Nakamura
authors.forename: Chizu
authors.initials: C
authors.lastname: Nakamoto
authors.forename: Hiroya
authors.initials: H
authors.lastname: Obama
authors.forename: Elaine
authors.initials: E
authors.lastname: Durward
authors.forename: Masaru
authors.initials: M
authors.lastname: Nakamoto
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000196:embryology*; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary; D019700:Thrombospondin 1
chemical_list: C491253:Nell2 protein, mouse; D009419:Nerve Tissue Proteins; D019700:Thrombospondin 1