CB27CH28-Ghosh ARI 10 September 2011 8:2 Role of Leucine-Rich Repeat Proteins in the Development and Function of Neural Circuits Joris de Wit,1,∗ Weizhe Hong,2,∗ Liqun Luo,2 and Anirvan Ghosh1 1Neurobiology Section, Division of Biology, University of California, San Diego, La Jolla, California 92093-0366; email: [email protected] 2Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, California 94305-5020; email: [email protected] Annu. Rev. Cell Dev. Biol. 2011. 27:697–729 Keywords First published online as a Review in Advance on axon guidance, target selection, synapse formation, cell adhesion, July 5, 2011 neural connectivity The Annual Review of Cell and Developmental Biology is online at cellbio.annualreviews.org Abstract This article’s doi: The nervous system consists of an ensemble of billions of neurons in- 10.1146/annurev-cellbio-092910-154111 terconnected in a highly specific pattern that allows proper propagation Copyright c 2011 by Annual Reviews. and integration of neural activities. The organization of these specific All rights reserved connections emerges from sequential developmental events including 1081-0706/11/1110-0697$20.00 axon guidance, target selection, and synapse formation. These events Annu. Rev. Cell Dev. Biol. 2011.27:697-729. Downloaded from www.annualreviews.org ∗These authors contributed equally to this critically rely on cell-cell recognition and communication mediated by manuscript. cell-surface ligands and receptors. Recent studies have uncovered cen- by Stanford University - Main Campus Robert Crown Law Library on 11/06/11. For personal use only. tral roles for leucine-rich repeat (LRR) domain-containing proteins, not only in organizing neural connectivity from axon guidance to tar- get selection to synapse formation, but also in various nervous system disorders. Their versatile LRR domains, in particular, serve as key sites for interactions with a wide diversity of binding partners. Here, we fo- cus on a few exquisite examples of secreted or membrane-associated LRR proteins in Drosophila and mammals and review the mechanisms by which they regulate diverse aspects of nervous system development and function. 697 CB27CH28-Ghosh ARI 10 September 2011 8:2 INTRODUCTION Contents Assembling a functional nervous system re- INTRODUCTION.................. 698 quires connecting neurons into circuits with ex- THE LEUCINE-RICH REPEAT . 698 traordinary precision. To accomplish this spe- LEUCINE-RICH REPEAT cific connectivity, axons and dendrites must PROTEINS IN NEURAL navigate toward their target regions, identify DEVELOPMENT................ 702 their appropriate target cells, and form synap- AXON GUIDANCE AND tic contacts with these cells. Along their trajec- DENDRITE ARBORIZATION . 702 tory toward their synaptic targets, neurites are Slit and Robo Regulate Axon guided by an array of secreted and membrane- Midline Crossing . 702 bound factors that help them navigate the com- Slit and Robo Regulate Axon plex extracellular environment and establish TractPositioning............... 705 contacts with other cells. Among the factors Slit and Robo Regulate Dendritic regulating the development of neural circuits, Arborization.................... 705 proteins containing extracellular leucine-rich Trk Receptors Regulate Axon repeat (LRR) domains have recently emerged Guidance . 706 as key organizers of connectivity. The LRR is TARGET SELECTION . 707 a protein-interaction motif that regulates axon Slit Controls Global Directional guidance, target selection, synapse formation, Targeting...................... 707 and stabilization of connections. In addition, re- Capricious Regulates Discrete cent work implicates LRR proteins in disorders Targeting...................... 708 of the nervous system. Other Leucine-Rich Repeat Proteins In this review, we highlight recent advances Involved in Target Selection. 710 in our understanding of the role of LRR pro- SYNAPSE FORMATION teins in the development, function, and disor- ANDFUNCTION................ 711 ders of neural circuits. We focus on secreted SALMs, NGLs, and LRRTMs and membrane-associated LRR proteins with Regulate Synapse Formation LRRs in their extracellular domain (listed in inVertebrates.................. 711 Table 1 and Figure 1). We have limited the LGI1 Regulates Synapse Function . 715 discussion to the fly and mammalian nervous MYELINATION..................... 716 systems because most of the experimental work LIMITING STRUCTURAL on the function of extracellular LRR (eLRR) PLASTICITY IN THE ADULT proteins has been done in these two model CENTRAL NERVOUS systems. SYSTEM.......................... 718 Annu. Rev. Cell Dev. Biol. 2011.27:697-729. Downloaded from www.annualreviews.org LEUCINE-RICH REPEAT PROTEINS AND DISORDERS THE LEUCINE-RICH REPEAT by Stanford University - Main Campus Robert Crown Law Library on 11/06/11. For personal use only. OF THE NERVOUS SYSTEM . 719 The LRR, one of the most common protein Slitrks in Tourette’s Syndrome and domain repeats across species (Bjorklund et al. Obsessive-Compulsive 2006), is a structural motif of 20 to 30 amino Disorder....................... 719 acids in length. The N-terminal part of the LGI1 in Epilepsy . 719 repeat consists of a conserved 11-residue se- NgR in Schizophrenia. 720 quence rich in leucines at defined positions Other Leucine-Rich Repeat Proteins (LxxLxLxxNxL, where x is any amino acid), al- in Nervous System Disorders . 720 though the leucine and asparagine residues can CONCLUDINGREMARKS......... 721 be substituted with other hydrophobic residues. This part of the motif forms a β-strand and a 698 de Wit et al. CB27CH28-Ghosh ARI 10 September 2011 8:2 Table 1 Leucine-rich repeat (LRR) proteins covered in this reviewa Membrane LRRb proteins topology Aspects of neural circuit development Binding partner Slit, Slit1-3 Secreted Axon guidance, dendrite arborization, target Robo receptors selection TrkA, TrkB, TrkC Transmembrane Axon guidance, neuronal survival, synapse Neurotrophins (NGF, NT3, NT4, formation BDNF), RPTPσ (TrkC) Linx/Islr2 Transmembrane Axon guidance TrkA, Ret Capricious Transmembrane Target selection Unknown Tartan Transmembrane Target selection Unknown Connectin GPI anchored Target selection Self Toll Transmembrane Target selection Spatzle NGL1, 2, 3 Transmembrane Synapse formation Netrin-G1, -G2 (NGL1, 2, respect- ively), LAR family RPTPs (NGL3) LRRTM1, 2, 3 Transmembrane Synapse formation, synapse function, nervous α-andβ-neurexins (-S4) system disorders (LRRTM1, 2) SALM2, 3, 5 Transmembrane Synapse formation Unknown LGI1 Secreted Synapse function, nervous system disorders ADAM22 LGI4 Secreted Myelination (PNS) ADAM22 LINGO-1 Transmembrane Myelination (CNS) Unknown NgR1 GPI anchored Limiting plasticity, nervous system disorders Nogo, MAG, OMgp OMgp GPI anchored Limiting plasticity NgR1 Slitrk1, 2 Transmembrane Nervous system disorders Unknown LRRN3 Transmembrane Nervous system disorders Unknown Tlr4 Transmembrane Nervous system disorders Pathogen-associated molecular patterns aRed: Drosophila LRR proteins; blue: mammalian LRR proteins. bAbbreviations: ADAM22, a disintegrin and metalloprotease domain 22; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; GPI, glycosylphosphatidylinositol; LAR, leukocyte common antigen-related; LGI, leucine-rich glioma inactivated; LINGO-1, LRR and Ig domain containing, Nogo-receptor-interacting protein 1; LRRN, LRR neuronal; LRRTM, LRR transmembrane; MAG, myelin-associated glycoprotein; NGF, nerve growth factor; NGL, netrin-G ligand; NT, neurotrophin; OMgp, oligodendrocyte-myelin glycoprotein; NgR, Nogo receptor; PNS, peripheral nervous system; RPTP, receptor protein tyrosine phosphatase; SALM, synaptic adhesion-like molecule; Slitrk, Slit and Trk-like; Tlr, Toll-like receptor. loop region that connects with the C-terminal each repeat contributes a β-strand. This is a part of the repeat, which is more variable in defining feature of all LRR domains. The con- Annu. Rev. Cell Dev. Biol. 2011.27:697-729. Downloaded from www.annualreviews.org sequence and structure (Kajava 1998; Kobe & vex side of ribonuclease inhibitor consists of Deisenhofer 1994, 1995a) (Figure 2a). Indi- α-helices, but composition can vary substan- by Stanford University - Main Campus Robert Crown Law Library on 11/06/11. For personal use only. vidual LRRs are arrayed in tandems of two tially in other LRR proteins (Bella et al. 2008). or more repeats that together constitute the The curved structure of the LRR domain and LRR domain. The first crystal structure of a the exposed β-sheet on the concave side form protein consisting entirely of LRRs, ribonucle- a large binding surface, which makes the LRR ase inhibitor, revealed that this arrangement in domain a very effective protein-binding motif multiple repeats results in a curved, horseshoe- (Kobe & Kajava 2001). The crystal structure shaped structure (Kobe & Deisenhofer 1993) of ribonuclease inhibitor in complex with its (Figure 2b). The concave side of this structure ligand RNase A first demonstrated that globular is made up of a continuous β-sheet, to which ligands can fit in the concave space formed by www.annualreviews.org • LRR Proteins in Neural Development 699 CB27CH28-Ghosh ARI 10 September 2011 8:2 a Axon guidance b Target selection c Synapse formation 3-4 Conn LGI1 3–4 NGL1 LRRTM1 SALM2 TrkA Linx/Islr2 Caps NGL2 LRRTM2 SALM3 TrkB Trn Toll NGL3 SALM5 TrkC 3–4 d Myelination e Limiting f Nervous system disorders e plasticity 9–10 1–3 10–11 Slit Slit-1 Slit-2 Slit-3 LGI4 NgR1