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Spatial memory formation requires netrin-1 expression by neurons in the adult mammalian brain. Wong Edwin W,Glasgow Stephen D,Trigiani Lianne J,Chitsaz Daryan,Rymar Vladimir,Sadikot Abbas,Ruthazer Edward S,Hamel Edith,Kennedy Timothy E Learning & memory (Cold Spring Harbor, N.Y.) Netrin-1 was initially characterized as an axon guidance molecule that is essential for normal embryonic neural development; however, many types of neurons continue to express netrin-1 in the postnatal and adult mammalian brain. Netrin-1 and the netrin receptor DCC are both enriched at synapses. In the adult hippocampus, activity-dependent secretion of netrin-1 by neurons potentiates glutamatergic synapse function, and is critical for long-term potentiation, an experimental cellular model of learning and memory. Here, we assessed the impact of neuronal expression of netrin-1 in the adult brain on behavior using tests of learning and memory. We show that adult mice exhibit impaired spatial memory following conditional deletion of netrin-1 from glutamatergic neurons in the hippocampus and neocortex. Further, we provide evidence that mice with conditional deletion of netrin-1 do not display aberrant anxiety-like phenotypes and show a reduction in self-grooming behavior. These findings reveal a critical role for netrin-1 expressed by neurons in the regulation of spatial memory formation. 10.1101/lm.049072.118
DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome. Marsh Ashley P L,Edwards Timothy J,Galea Charles,Cooper Helen M,Engle Elizabeth C,Jamuar Saumya S,Méneret Aurélie,Moutard Marie-Laure,Nava Caroline,Rastetter Agnès,Robinson Gail,Rouleau Guy,Roze Emmanuel,Spencer-Smith Megan,Trouillard Oriane,Billette de Villemeur Thierry,Walsh Christopher A,Yu Timothy W, ,Heron Delphine,Sherr Elliott H,Richards Linda J,Depienne Christel,Leventer Richard J,Lockhart Paul J Human mutation The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC). 10.1002/humu.23361
MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation. Brudvig J J,Cain J T,Schmidt-Grimminger G G,Stumpo D J,Roux K J,Blackshear P J,Weimer J M Molecular neurobiology Axons of the corpus callosum (CC), the white matter tract that connects the left and right hemispheres of the brain, receive instruction from a number of chemoattractant and chemorepulsant cues during their initial navigation towards and across the midline. While it has long been known that the CC is malformed in the absence of Myristoylated alanine-rich C-kinase substrate (MARCKS), evidence for a direct role of MARCKS in axon navigation has been lacking. Here, we show that MARCKS is necessary for Netrin-1 (NTN1) signaling through the DCC receptor, which is critical for axon guidance decisions. Marcks null (Marcks) neurons fail to respond to exogenous NTN1 and are deficient in markers of DCC activation. Without MARCKS, the subcellular distributions of two critical mediators of NTN1-DCC signaling, the tyrosine kinases PTK2 and SRC, are disrupted. Together, this work establishes a novel role for MARCKS in axon dynamics and highlights the necessity of MARCKS as an organizer of DCC signaling at the membrane. 10.1007/s12035-018-0990-3
Netrin-1/DCC-mediated PLCγ1 activation is required for axon guidance and brain structure development. Kang Du-Seock,Yang Yong Ryoul,Lee Cheol,Park BumWoo,Park Kwang Il,Seo Jeong Kon,Seo Young Kyo,Cho HyungJoon,Lucio Cocco,Suh Pann-Ghill EMBO reports Coordinated expression of guidance molecules and their signal transduction are critical for correct brain wiring. Previous studies have shown that phospholipase C gamma1 (PLCγ1), a signal transducer of receptor tyrosine kinases, plays a specific role in the regulation of neuronal cell morphology and motility However, several questions remain regarding the extracellular stimulus that triggers PLCγ1 signaling and the exact role PLCγ1 plays in nervous system development. Here, we demonstrate that PLCγ1 mediates axonal guidance through a netrin-1/deleted in colorectal cancer (DCC) complex. Netrin-1/DCC activates PLCγ1 through Src kinase to induce actin cytoskeleton rearrangement. Neuronal progenitor-specific knockout of in mice causes axon guidance defects in the dorsal part of the mesencephalon during embryogenesis. Adult -deficient mice exhibit structural alterations in the corpus callosum, substantia innominata, and olfactory tubercle. These results suggest that PLCγ1 plays an important role in the correct development of white matter structure by mediating netrin-1/DCC signaling. 10.15252/embr.201846250