Identification and expression of mouse netrin-4

Yin, Yong; Sanes, Joshua R.; Miner, Jeffrey H.

doi:10.1016/s0925-4773(00)00369-5

Cited by 87 publications

(79 citation statements)

References 19 publications

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“…S1 A]. Similarity BLAST search analysis of peptides displayed by the enriched phage population showed that the sequence CGLPYSSVC contained a motif embedded within domain IV of the netrin-4 protein (Leu-404-Val-410) (9,10). Detailed sequence alignment revealed that the region mimicked by the peptide motif is not similar to any other known member of the netrin and laminin families of proteins (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Yet, with critical roles in tissue morphogenesis (2)(3)(4), vascular patterning (5), and angiogenesis (6)(7)(8), netrins have become recognized to mediate functions far beyond axonal guidance. Netrin-4 is expressed in both neural and nonneural tissues (8)(9)(10)(11). In the nervous system, it promotes neurite extension from olfactory bulb (OB) explants but the molecular mechanisms underlying this phenomenon remain unknown.…”

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confidence: 99%

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Discovery of a functional protein complex of netrin-4, laminin γ1 chain, and integrin α6β1 in mouse neural stem cells

Staquicini

Dias-Neto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Molecular and cellular interactions coordinating the origin and fate of neural stem cells (NSCs) in the adult brain are far from being understood. We present a protein complex that controls proliferation and migration of adult NSCs destined for the mouse olfactory bulb (OB). Combinatorial selection based on phage display technology revealed a previously unrecognized complex between the soluble protein netrin-4 and laminin ␥1 subunit that in turn activates an ␣6␤1 integrin-mediated signaling pathway in NSCs. Differentiation of NSCs is accompanied by a decrease in netrin-4 receptors, indicating that netrin-4 participates in the continual propagation of this stem cell population. Notably, the stem cells themselves do not synthesize netrin-4. Further, we show that netrin-4 is produced by selected GFAP-positive astrocytes positioned close to newborn neurons migrating in the anterior part of the rostral migratory stream (RMS) and within the OB. Our findings present a unique molecular mechanism mediating astrocytic/neuronal crosstalk that regulates ongoing neurogenesis in the adult olfactory system. olfactory system ͉ phage display ͉ merogenesis ͉ rostral migratory stream ͉ astrocytes N etrins are a family of secreted proteins initially described as developmental axon attractants (1). Yet, with critical roles in tissue morphogenesis (2-4), vascular patterning (5), and angiogenesis (6-8), netrins have become recognized to mediate functions far beyond axonal guidance. Netrin-4 is expressed in both neural and nonneural tissues (8-11). In the nervous system, it promotes neurite extension from olfactory bulb (OB) explants but the molecular mechanisms underlying this phenomenon remain unknown. In the vasculature of the kidney, heart, and ovary, the protein is located in the basement membrane. Integrins and netrins, along with the established netrin-1 and netrin-4 receptors DCC and UNC5, appear to cooperate to regulate multiple aspects of development (3,12,13). However, certain netrin-4 functions are mediated by neogenin (8) and likely by other, as yet unidentified receptors (14, 15).Here, we provide evidence for a direct relationship between netrin-4, laminin ␥1 chain, and ␣6␤1 integrin in the context of neural stem cells (NSCs). By exploiting the power of the unbiased phage display combinatorial approach (16-18), followed by peptide affinity chromatography and functional validation, we found that a netrin-4/laminin ␥1 chain complex binds to ␣6␤1 integrin, with subsequent activation of the mitogenactivated protein (MAP) kinase signaling pathway, resulting in NSC migration and proliferation. We also show that in the adult mouse brain, netrin-4 is produced by a subset of astrocytes on the edge of the rostral migratory system (RMS) close to the site of neuron entrance into the OB. Our findings support the conclusion that netrin-4 is a regulatory factor in NSC biology and uncover a previously unrecognized mechanism in which a multimeric complex functions as an integrated supramolecular switch that regulates NSC fate. Results and...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of a functional protein complex of netrin-4, laminin γ1 chain, and integrin α6β1 in mouse neural stem cells

Staquicini

Dias-Neto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Netrin-1 also was found to be a ligand for integrin a3b1 with the interaction implicated in neuronal migration (Stanco et al 2009). Netrin-4, a more distantly related member with greatest homology with the b-laminin short arm (Yin et al 2000) and widely expressed in basement membranes of developing tissues, has been found to inhibit laminin-111 polymerization, evidence for a binding interaction with the laminin LN domains (Schneiders et al 2007). …”

Section: Other Basement Membrane Componentsmentioning

confidence: 99%

Basement Membranes: Cell Scaffoldings and Signaling Platforms

Yurchenco

2010

Cold Spring Harbor Perspectives in Biology

780

775

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“…129 The biochemical purification of this attractant led to the identification of netrin-1, a laminin related protein, 130 whose function in regulating axon guidance at the midline of the nervous system is conserved in evolution. 3 There are at least three netrin genes in mammals (netrin-1, netrin-3/ NTN2L and netrin-4 [131][132][133][134] ). Netrin-1 can attract several classes of axons throughout the developing nervous system but also acts as a repulsive factor for some axons.…”

Section: Netrins and Their Receptorsmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

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Identification and expression of mouse netrin-4

Cited by 87 publications

References 19 publications

Discovery of a functional protein complex of netrin-4, laminin γ1 chain, and integrin α6β1 in mouse neural stem cells

Discovery of a functional protein complex of netrin-4, laminin γ1 chain, and integrin α6β1 in mouse neural stem cells

Basement Membranes: Cell Scaffoldings and Signaling Platforms

The brain within the tumor: new roles for axon guidance molecules in cancers

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