28

2013 May

Serotonin signaling in the brain of adult female mice is required for sexual preference

Zhang S, Liu Y, Rao Y.

Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9968-73.

A role for serotonin in male sexual preference was recently uncovered by our finding that male mutant mice lacking serotonin have lost sexual preference. Here we show that female mouse mutants lacking either central serotonergic neurons or serotonin prefer female over male genital odors when given a choice, and displayed increased female-female mounting when presented either with a choice of a male and a female target or only with a female target. Pharmacological manipulations and genetic rescue experiments showed that serotonin is required in adults. Behavioral changes caused by deficient serotonergic signaling were not due to changes in plasma concentrations of sex hormones. We demonstrate that a genetic manipulation reverses sexual preference without involving sex hormones. Our results indicate that serotonin controls sexual preference. https://www.pnas.org/doi/10.1073/pnas.1220712110?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed
10

2012 Oct

Molecular Genetic Analysis of Sexual Rejection: Roles of Octopamine and Its Receptor OAMB in Drosophila Courtship Conditioning

Zhou C*, Huang H*, Kim SM*, Lin H, Meng X, Han KA, Chiang AS, Wang JW, Jiao R, Rao Y.

J Neurosci. 2012 Oct 10;32(41):14281-7.

After Drosophila males are rejected by mated females, their subsequent courtship is inhibited even when encountering virgin females. Molecular mechanisms underlying courtship conditioning in the CNS are unclear. In this study, we find that tyramine β hydroxylase (TβH) mutant males unable to synthesize octopamine (OA) showed impaired courtship conditioning, which could be rescued by transgenic TβH expression in the CNS. Inactivation of octopaminergic neurons mimicked the TβH mutant phenotype. Transient activation of octopaminergic neurons in males not only decreased their courtship of virgin females, but also produced courtship conditioning. Single cell analysis revealed projection of octopaminergic neurons to the mushroom bodies. Deletion of the OAMB gene encoding an OA receptor expressed in the mushroom bodies disrupted courtship conditioning. Inactivation of neurons expressing OAMB also eliminated courtship conditioning. OAMB neurons responded robustly to male-specific pheromone cis-vaccenyl acetate in a dose-dependent manner. Our results indicate that OA plays an important role in courtship conditioning through its OAMB receptor expressed in a specific neuronal subset of the mushroom bodies. https://www.jneurosci.org/content/32/41/14281.long
19

2011 Jun

Social regulation of aggression by pheromonal activation of Or65a olfactory neurons in Drosophila

Liu W*, Liang X*, Gong J, Yang Z, Zhang YH, Zhang JX, Rao Y.

Nat Neurosci. 2011 Jun 19;14(7):896-902.

When two socially naive Drosophila males meet, they will fight. However, prior social grouping of males reduces their aggression. We found olfactory communication to be important for modulating Drosophila aggression. Although acute exposure to the male-specific pheromone 11-cis-vaccenyl acetate (cVA) elicited aggression through Or67d olfactory receptor neurons (ORNs), chronic cVA exposure reduced aggression through Or65a ORNs. Or65a ORNs were not acutely involved in aggression, but blockade of synaptic transmission of Or65a ORNs during social grouping or prior chronic cVA exposure eliminated social modulation of aggression. Artificial activation of Or65a ORNs by ectopic expression of the Drosophila gene TrpA1 was sufficient to reduce aggression. Social suppression of aggression requires subsets of local interneurons in the antennal lobe. Our results indicate that activation of Or65a ORNs is important for social modulation of male aggression, demonstrate that the acute and chronic effects of a single pheromone are mediated by two distinct types of ORNs, reveal a behaviorally important role for interneurons and suggest a chemical method to reduce aggression in animals. https://www.nature.com/articles/nn.2836
07

2011 Apr

Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice

Liu Y*, Jiang Y*, Si Y, Kim JY, Chen ZF, Rao Y.

Nature. 2011 Apr 7;472(7341):95-9.

Although the question of to whom a male directs his mating attempts is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference. https://www.nature.com/articles/nature09822
01

2008 Aug

A subset of octopaminergic neurons are important for Drosophila aggression

Zhou C, Rao Y, Rao Y.

Nat Neurosci. 2008 Sep;11(9):1059-67.

Aggression is an innate behavior that is important for animal survival and evolution. We examined the molecular and cellular mechanisms underlying aggression in Drosophila. Reduction of the neurotransmitter octopamine, the insect equivalent of norepinephrine, decreased aggression in both males and females. Mutants lacking octopamine did not initiate fighting and did not fight other flies, although they still provoked other flies to fight themselves. Mutant males lost to the wild-type males in fighting and in competing for copulation with females. Enhanced octopaminergic signaling increased aggression in socially grouped flies, but not in socially isolated flies. We carried out genetic rescue experiments that revealed the functional importance of neuronal octopamine and identified a small subset of octopaminergic neurons in the suboesophageal ganglion as being important for aggression. https://www.nature.com/articles/nn.2164
09

2007 Dec

Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling

Li X, Gao X, Liu G, Xiong W, Wu J, Rao Y.

Nat Neurosci. 2008 Jan;11(1):28-35.

Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1. https://www.nature.com/articles/nn2022
15

2007 Jun

Role of the integrin-linked kinase (ILK) in determining neuronal polarity

Guo W, Jiang H, Gray V, Dedhar S, Rao Y.

Dev Biol. 2007 Jun 15;306(2):457-68.

The establishment of axon-dendrite polarity in mammalian neurons has recently been shown to involve the kinases Akt and GSK-3beta. Here we report the function of the integrin-linked kinase (ILK) in neuronal polarization. ILK distribution is differential: with more of it present in the axonal tips than that in the dendritic tips of a polarized neuron. Inactivation of ILK by chemical inhibitors, a kinase-inactive mutant or siRNAs inhibited axon formation, whereas a kinase hyperactive ILK mutant induced the formation of multiple axons. Biochemical studies indicate that ILK is upstream of Akt and GSK-3beta. Manipulations of multiple intracellular components indicate that ILK is functionally upstream of Akt and GSK-3beta but downstream of PI3K in neuronal polarity. These results reveal a key role of ILK in the formation of neuronal polarity and suggest a signaling pathway important for neuronal polarity. https://linkinghub.elsevier.com/retrieve/pii/S0012-1606(07)00220-5
14

2005 Jan

Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3b and its upstream regulators

Jiang H, Guo W, Liang X, Rao Y.

Cell. 2005 Jan 14;120(1):123-35.

Axon-dendrite polarity is a cardinal feature of neuronal morphology essential for information flow. Here we report a differential distribution of GSK-3beta activity in the axon versus the dendrites. A constitutively active GSK-3beta mutant inhibited axon formation, whereas multiple axons formed from a single neuron when GSK-3beta activity was reduced by pharmacological inhibitors, a peptide inhibitor, or siRNAs. An active mechanism for maintaining neuronal polarity was revealed by the conversion of preexisting dendrites into axons upon GSK-3 inhibition. Biochemical and functional data show that the Akt kinase and the PTEN phosphatase are upstream of GSK-3beta in determining neuronal polarity. Our results demonstrate that there are active mechanisms for maintaining as well as establishing neuronal polarity, indicate that GSK-3beta relays signaling from Akt and PTEN to play critical roles in neuronal polarity, and suggest that application of GSK-3beta inhibitors can be a novel approach to promote generation of new axons after neural injuries. https://linkinghub.elsevier.com/retrieve/pii/S0092867404012589
17

2004 Oct

Netrin requires the focal adhesion kinase and the Src family kinases to induce axon outgrowth and to attract axons

Liu G, Beggs H, Jürgensen C, Park HT, Tang H, Gorski J, Jones KR, Reichardt LF, Wu J, Rao Y.

Nat Neurosci. 2004 Nov;7(11):1222-32.

Although netrins are an important family of neuronal guidance proteins, intracellular mechanisms that mediate netrin function are not well understood. Here we show that netrin-1 induces tyrosine phosphorylation of proteins including focal adhesion kinase (FAK) and the Src family kinase Fyn. Blockers of Src family kinases inhibited FAK phosphorylation and axon outgrowth and attraction by netrin. Dominant-negative FAK and Fyn mutants inhibited the attractive turning response to netrin. Axon outgrowth and attraction induced by netrin-1 were significantly reduced in neurons lacking the FAK gene. Our results show the biochemical and functional links between netrin, a prototypical neuronal guidance cue, and FAK, a central player in intracellular signaling that is crucial for cell migration. https://www.nature.com/articles/nn1331
27

2004 Jan

Visualization of spatially and temporally regulated N-WASP activity during cytoskeletal reorganization in living cells

Ward ME, Wu JY, Rao Y.

Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):970-4.

Members of the WASP/WAVE family of proteins are key regulators of cytoskeletal reorganization across a diverse range of cellular processes. Despite a wealth of biochemical data about WASP/WAVE regulation in vitro, our understanding of the in vivo regulation of these proteins is hampered by the inability to monitor subcellular regulation of their activities in living cells. Here we establish a fluorescence resonance energy transfer-based approach to visualize spatial and temporal regulation of neuronal Wiskott-Aldrich syndrome protein (N-WASP) activity in living cells. Using time-lapse microscopy, we characterize the activation of N-WASP in response to growth-factor stimulation, and we reveal that N-WASP is activated inside extending filopodia. Furthermore, we suggest a role of N-WASP in regulating membrane ruffling downstream of phosphatidylinositol 4,5-bisphosphate and Cdc42. https://www.pnas.org/doi/10.1073/pnas.0306258101?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed
24

2002 Jun

Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons

Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, Rao Y.

Nat Neurosci. 2002 Aug;5(8):719-20.

Migration of neuronal precursor cells from the external germinal layer (EGL) to the internal granular layer (IGL) is a crucial process in the development of the mammalian cerebellar cortex. These cells make up the only precursor population known to migrate away from the surface of the brain. We studied the role of the chemokine stromal-derived factor 1 (SDF-1) in the cerebellar tissue of rats and knockout mice and found (i) that it functions as an attractive guidance cue for neuronal migration and (ii) that its secretion from non-neuronal meningeal tissue is important for controlling the migration of embryonic EGL cells. https://www.nature.com/articles/nn881
19

2001 Oct

Signal Transduction in Neuronal Migration: Roles of GTPase Activating Proteins and the Small GTPase Cdc42 in the Slit-Robo Pathway

Wong K, Ren XR, Huang YZ, Xie Y, Liu G, Saito H, Tang H, Wen L, Brady-Kalnay SM, Mei L, Wu JY, Xiong WC, Rao Y.

Cell. 2001 Oct 19;107(2):209-21.

The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo). We report here that the intracellular domain of Robo interacts with a novel family of Rho GTPase activating proteins (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions responsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) of the forebrain. A constitutively active Cdc42 blocked the repulsive effect of Slit. These results have demonstrated important roles for GAPs and Cdc42 in neuronal migration. We propose a signal transduction pathway from the extracellular guidance cue to intracellular actin polymerization.
19

2001 Apr

The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors

Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H, Bacon KB, Jiang Zh, Zhang Xc, Rao Y.

Nature. 2001 Apr 19;410(6831):948-52.

Migration is a basic feature of many cell types in a wide range of species. Since the 1800s, cell migration has been proposed to occur in the nervous and immune systems, and distinct molecular cues for mammalian neurons and leukocytes have been identified. Here we report that Slit, a secreted protein previously known for its role of repulsion in axon guidance and neuronal migration, can also inhibit leukocyte chemotaxis induced by chemotactic factors. Slit inhibition of the chemokine-induced chemotaxis can be reconstituted by the co-expression of a chemokine receptor containing seven transmembrane domains and Roundabout (Robo), a Slit receptor containing a single transmembrane domain. Thus, there is a functional interaction between single and seven transmembrane receptors. Our results reveal the activity of a neuronal guidance cue in regulating leukocyte migration and indicate that there may be a general conservation of guidance mechanisms underlying metazoan cell migration. In addition, we have uncovered an inhibitor of leukocyte chemotaxis, and propose a new therapeutic approach to treat diseases involving leukocyte migration and chemotactic factors. https://www.nature.com/articles/35073616
22

1999 Jul

Directional guidance of neuronal migration in the olfactory system by the protein Slit

Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu JY, Rao Y.

Nature. 1999 Jul 22;400(6742):331-6.

Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration have remained unclear. Here we report that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Our results provide a direct demonstration of a molecular cue whose concentration gradient guides the direction of migrating neurons. They also support a common guidance mechanism for axon projection and neuronal migration and suggest that Slit may provide a molecular tool with potential therapeutic applications in controlling and directing cell migration. https://www.nature.com/articles/22477
19

1999 Mar

Vertebrate Slit, a secreted ligand for the transmembrane protein Roundabout, is a repellent for olfactory bulb axons

Li HS, Chen JH, Wu W, Fagaly T, Zhou L, Yuan W, Dupuis S, Jiang ZH, Nash W, Gick C, Ornitz DM, Wu JY, Rao Y.

Cell. 1999 Mar 19;96(6):807-18.

The olfactory bulb plays a central role in olfactory information processing through its connections with both peripheral and cortical structures. Axons projecting from the olfactory bulb to the telencephalon are guided by a repulsive activity in the septum. The molecular nature of the repellent is not known. We report here the isolation of vertebrate homologs of the Drosophila slit gene and show that Slit protein binds to the transmembrane protein Roundabout (Robo). Slit is expressed in the septum whereas Robo is expressed in the olfactory bulb. Functionally, Slit acts as a chemorepellent for olfactory bulb axons. These results establish a ligand-receptor relationship between two molecules important for neural development, suggest a role for Slit in olfactory bulb axon guidance, and reveal the existence of a new family of axon guidance molecules. https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(00)80591-7
01

1997 Feb

A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate

Li H, Tierney C, Wen L, Wu JY, Rao Y.

Development. 1997 Feb;124(3):603-15.

Two bilaterally symmetric eyes arise from the anterior neural plate in vertebrate embryos. An interesting question is whether both eyes share a common developmental origin or they originate separately. We report here that the expression pattern of a new gene ET reveals that there is a single retina field which resolves into two separate primordia, a suggestion supported by the expression pattern of the Xenopus Pax-6 gene. Lineage tracing experiments demonstrate that retina field resolution is not due to migration of cells in the median region to the lateral parts of the field. Removal of the prechordal mesoderm led to formation of a single retina both in chick embryos and in Xenopus explants. Transplantation experiments in chick embryos indicate that the prechordal plate is able to suppress Pax-6 expression. Our results provide direct evidence for the existence of a single retina field, indicate that the retina field is resolved by suppression of retina formation in the median region of the field, and demonstrate that the prechordal plate plays a primary signaling role in retina field resolution. https://journals.biologists.com/dev/article/124/3/603/39697/A-single-morphogenetic-field-gives-rise-to-two
11

1990 May

Similarity of the product of the Drosophila neurogenic gene big brain to transmembrane channel proteins

Rao Y, Jan LY, Jan YN.

Nature. 1990 May 10;345(6271):163-7.

Cells in the neurogenic region of Drosophila embryos are initially bipotential; they can become either neuroblasts or epidermoblasts. Cell-cell interaction seems to play an important part in this developmental decision, which involves the function of a group of genes (the neurogenic genes). Loss-of-function mutations in any of the neurogenic genes result in nervous system hyperplasia and epidermal hypoplasia. Of the six known zygotic neurogenic genes, big brain (bib) is unique in several aspects. Most notably, all the other known neurogenic genes seem to fit into a cascade defined by genetic interactions, whereas bib does not show any detectable interaction with them. To understand how bib functions, we have now cloned the bib genomic and complementary DNAs. The predicted bib product shows significant sequence similarity to a family of transmembrane proteins, some of which form channels permeable to small molecules. Together with genetic studies, our results indicate that the bib product may mediate intercellular communication in a pathway separate from the one involving the products of the other neurogenic genes. https://www.nature.com/articles/345163a0

1 2

Home