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Pre-and postsynaptic recognition is Dscam independent. (A) Schematic showing ORN/PN/LN matching in olfactory lobes of Drosophila in wild type and Dscam mutants. (B-E) ORN-PN matching identities remain in Dscam mutants. Mz-19 positive PN dendrites connect to axons of ORN class 88a (D) and not to 47b (B) in wild type. In Dscam mutant, the dendrites follow the misprojecting 88a axons (E) but avoid ectopic 47b axons (C). (F-J) GH146 expressing dendrites do not innervate ectopic Dscam mutant ORN 47a spots, when they are far away from the wild type glomerulus (box in H, compared to F). Ectopic spots of ORN46a axons outside of the AL are not innervated by GH146-positive dendrites (G,J) even if the glomerulus of the ORN46a class is innervated by GH146-positive dendrites. (K-N) Ectopic Dscam mutant spots are innervated from C753-positive LNs in the AL in case of ORN21a (L) as well as outside the AL in case of ORN46a (N). Green: sytGFP, red: ratCD2, blue: Toto3. Scale bar: 25 µm. Genotype: (B) eyflp UAS-CD2; FRT42/FRT42 PCNA; 47b::sytGFP Mz19-Gal4 UAS-CD2. (C) eyflp UAS-CD2; FRT42 Dscam/FRT42 PCNA; 47b::sytGFP Mz19-Gal4 UAS-CD2. (D) eyflp UAS-CD2; FRT42/FRT42 PCNA; 88a::sytGFP Mz19-Gal4 UAS-CD2. (E) eyflp UAS-CD2; FRT42 Dscam/FRT42 PCNA; 88a::sytGFP Mz19-Gal4 UAS-CD2. (F-G) eyflp UAS-CD2; FRT42 OR::sytGFP/ FRT42 PCNA; GH146-Gal4 UAS-CD2. (H-J) eyflp UAS-CD2; FRT42 Dscam OR::sytGFP/FRT42 PCNA; GH146-Gal4 UAS-CD2. (K,M) eyflp UAS-CD2; FRT42 OR::sytGFP/FRT42 PCNA; C753-Gal4 UAS-CD2. (L,N) eyflp UAS-CD2; FRT42 Dscam OR::sytGFP/FRT42 PCNA; C753-Gal4 UAS-CD2.
Source publication
Olfactory systems across the animal kingdom show astonishing similarities in their morphological and functional organization. In mouse and Drosophila, olfactory sensory neurons are characterized by the selective expression of a single odorant receptor (OR) type and by the OR class-specific connection in the olfactory brain center. Monospecific OR e...
Contexts in source publication
Context 1
... all ORN specific Dscam mosaics with large mutant clones that show a local rearrangement of the glomerular position (ORN47a/22a n = 14; ORN47b/88a n = 22), axons of different ORN classes do not intermingle but segregate according to the OR identity. To determine the OR class identity of distant ectopic glomeruli we combined a broad ORN marker and a non-overlapping single OR class marker (Supplementary Fig. S2). In all of the analyzed ORN specific Dscam mutant mosaic brains (Con > CD2/OR:sytGFP, n > 10 per OR class; MT14 > CD2/OR:sytGFP, n = 10 per OR class) ectopic glomeruli in different regions of the antennal lobe target area maintain their single ORN-class identity. ...
Context 2
... local reorganization of the glomerular field, in which ORN88a glomeruli are often displaced by neighboring ORN47b axons (compare Fig. 1E,F). In all analyzed Dscam mosaic brains (n > 10), the changes in glomerulus localization lead to a corresponding shift in the PN dendritic field, ensuring that the class-specific ORN-PN matching is maintained ( Fig. 2B-E). For more distant ectopic glomeruli we characterized the innervation of Dscam mutant ORN axons with GH146-positive PN dendrites, which cover all regions of the AL. The ORN classes 21a and 47a, which are not innervated by GH146-positive PNs in wild type, form ectopic glomeruli in Dscam mosaics but do not receive GH146-innervation (Fig. ...
Context 3
... ( Fig. 2B-E). For more distant ectopic glomeruli we characterized the innervation of Dscam mutant ORN axons with GH146-positive PN dendrites, which cover all regions of the AL. The ORN classes 21a and 47a, which are not innervated by GH146-positive PNs in wild type, form ectopic glomeruli in Dscam mosaics but do not receive GH146-innervation (Fig. 2F,H, Supplementary Fig. S4; n > 40). In addition, the Dscam mutant maxillary ORN 46a that converge outside the AL are never associated with GH146-positive PN dendrites although in wild type this ORN class connects to GH146-PNs ( Fig. 2G,J; n = 6). ...
Context 4
... by GH146-positive PNs in wild type, form ectopic glomeruli in Dscam mosaics but do not receive GH146-innervation (Fig. 2F,H, Supplementary Fig. S4; n > 40). In addition, the Dscam mutant maxillary ORN 46a that converge outside the AL are never associated with GH146-positive PN dendrites although in wild type this ORN class connects to GH146-PNs ( Fig. 2G,J; n = 6). ...
Context 5
... generate small PN clones, Supplementary www.nature.com/scientificreports www.nature.com/scientificreports/ To test if ectopic glomeruli are accessible for postsynaptic neurites we analyzed their interaction with local interneurons (LNs). In the wild type AL, LNs do not display glomerulus-specificity but elaborate their neurites throughout the AL (Fig. 2K,M). In ORN-specific large Dscam mosaic brains, each of the ectopic glomeruli inside the AL receives postsynaptic innervation from LNs (n = 20 per OR class), indicating that the distant ectopic ORN axons are able to interact with the neurites. Furthermore, even the Dscam mutant ectopic glomeruli that are formed adjacent to the AL attracts ...
Context 6
... ORN-specific large Dscam mosaic brains, each of the ectopic glomeruli inside the AL receives postsynaptic innervation from LNs (n = 20 per OR class), indicating that the distant ectopic ORN axons are able to interact with the neurites. Furthermore, even the Dscam mutant ectopic glomeruli that are formed adjacent to the AL attracts LN neurites ( Fig. 2K-N; n = ...
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The singular expression of insect olfactory receptors in specific populations of olfactory sensory neurons is fundamental to the encoding of odors in patterns of neuronal activity in the brain. How a receptor gene is selected, from among a large repertoire in the genome, to be expressed in a particular neuron is an outstanding question. Focusing on...
Citations
... The litany of cell surface proteins implicated in olfactory system development, such as Semaphorins, DSCAM, Tenascins/Teneurins and Toll receptors, suggests that ORN class-specific cell surface codes are the main drivers of this topographic circuit assembly. 9,11,[13][14][15][16][17][18] Though there are several examples of cell surface molecules regulating ORN class-specific axon organization, it is still unclear when and how ORN class-specific axon convergence occurs during olfactory circuit development. 4,15,16,19 Given the importance of cell surface combinatorial codes, identifying novel cell surface proteins functionally required for olfactory circuit assembly is critical to decrypting the ''rosetta stone'' needed to translate cell surface signatures into predictable discrete cellular processes. ...
... 9,11,[13][14][15][16][17][18] Though there are several examples of cell surface molecules regulating ORN class-specific axon organization, it is still unclear when and how ORN class-specific axon convergence occurs during olfactory circuit development. 4,15,16,19 Given the importance of cell surface combinatorial codes, identifying novel cell surface proteins functionally required for olfactory circuit assembly is critical to decrypting the ''rosetta stone'' needed to translate cell surface signatures into predictable discrete cellular processes. Given the close association between the evolution of Cadherin family proteins and the emergence of the synapse, 20 it is unsurprising that members of the Cadherin family (N-cadherin and protocadherins) have been shown to regulate aspects of neuronal organization, 21 and specifically insect and mammalian olfactory circuit development. ...
The process of how neuronal identity confers circuit organization is intricately related to the mechanisms underlying neurodegeneration and neuropathologies. Modeling this process, the olfactory circuit builds a functionally organized topographic map, which requires widely dispersed neurons with the same identity to converge their axons into one a class-specific neuropil, a glomerulus. In this article, we identified Fat2 (also known as Kugelei) as a regulator of class-specific axon organization. In fat2 mutants, axons belonging to the highest fat2-expressing classes present with a more severe phenotype compared to axons belonging to low fat2-expressing classes. In extreme cases, mutations lead to neural degeneration. Lastly, we found that Fat2 intracellular domain interactors, APC1/2 (Adenomatous polyposis coli) and dop (Drop out), likely orchestrate the cytoskeletal remodeling required for axon condensation. Altogether, we provide a potential mechanism for how cell surface proteins’ regulation of cytoskeletal remodeling necessitates identity specific circuit organization.
... Within 18 h of puparium formation, after pioneering sensory neurons permeate the AL, OSNs converge on their target glomerulus and connect with PNs. Molecular mechanisms, such as the adhesion molecules N-cadherin and Dscam, enable class-specific OSN axon sorting (Zhu & Luo, 2004;Goyal et al., 2019) and synaptogenesis is initiated after OSNs recognize PN dendritic cues (Zhu et al., 2006). Although PNs are necessary for correct patterning of the AL in Drosophila, it has been demonstrated that glomeruli in Manduca also form after individual PN clusters are surgically removed (Oland & Tolbert, 1998). ...
p>Pheromones are pivotal to sexual communication in insects. These chemical signals are processed by sexually dimorphic circuitries in the antennal lobe (AL) of the insect brain. However, there is limited understanding of how these circuitries form during AL development. Our review addresses this issue by comparing how circuitries develop throughout the growth processes of peripheral and deutocerebral neurons in various insect orders. Olfactory sensory neurons (OSNs) expressing novel pheromone receptors are eligible candidates to initiate new sexually-dimorphic circuitries when these OSNs survive programmed cell death and match the physiological properties of pheromone-sensing sensilla. The probability of these OSNs forming new glomeruli is largely determined by the degree of glia-OSN interactions and projection neuron (PN) prepatterning. The relative contribution of either of these processes determines the degree of evolutionary neuroplasticity, which is particularly prevalent in those species with complex ALs lacking specific macroglomerular structures. The extent of sexual dimorphism is determined by sex-determination genes, such as Doublesex and Fruitless, that regulate factors inducing OSN programmed cell death. Currently, these mechanisms are largely unexplored. This review, therefore, aims to provide a solid foundation for ongoing research into the evolution of AL sexual dimorphism and formation of pheromone circuitries in the light of insect sex determination.</p
... Interestingly, Sema3F and its receptor Neuropilin-2 (Nrp2) are expressed in a complementary graded manner along the dorso-ventral axis in OSNs. Early-arriving dorsomedial axons exhibit high levels of Sema3F, and later-arriving ventrolateral axons express high levels of Nrp2 [120]. Selective inactivation of Sema3F in OSNs does not affect the sorting of dorsomedial and ventrolateral axons en route to the OB, but it causes Nrp2-expressing axons to mistarget to the dorsal region of the OB upon arrival. ...
... disorganized, tangled, and clumped together in mice lacking PcdhαC2. This phenotype could also be observed upon specific ablation of PcdhαC2 in serotonergic neurons [120], suggesting that Pcdhαc2 mediates homophilic repulsive interactions to promote tiling between serotonergic axon terminals. Interestingly, the Pcdhα gene cluster has been associated with schizophrenia and autism spectrum disorders, suggesting the possible involvement of defective trans-axonal signaling in the etiology of these neurodevelopmental disorders. ...
... While serotonergic axon terminals are precisely ordered and evenly spaced in their target fields in the basal ganglia and hippocampus, they appear disorganized, tangled, and clumped together in mice lacking PcdhαC2. This phenotype could also be observed upon specific ablation of PcdhαC2 in serotonergic neurons [120], suggesting that Pcdhαc2 mediates homophilic repulsive interactions to promote tiling between serotonergic axon terminals. Interestingly, the Pcdhα gene cluster has been associated with schizophrenia and autism spectrum disorders, suggesting the possible involvement of defective trans-axonal signaling in the etiology of these neurodevelopmental disorders. ...
The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation.
The formation and precise positioning of axons and dendrites are crucial for the development of neural circuits. Although juxtacrine signaling via cell–cell contact is known to influence these processes, the specific structures and mechanisms regulating neuronal process positioning within the central nervous system (CNS) remain to be fully identified. Our study investigates motoneuron 24 (MN24) in the Drosophila embryonic CNS, which is characterized by a complex yet stereotyped axon projection pattern, known as “axonal routing.” In this motoneuron, the primary dendritic branches project laterally toward the midline, specifically emerging at the sites where axons turn. We observed that Scp2-positive neurons contribute to the lateral fascicle structure in the ventral nerve cord (VNC) near MN24 dendrites. Notably, the knockout of the Down syndrome cell adhesion molecule ( Dscam1 ) results in the loss of dendrites and disruption of proper axonal routing in MN24, while not affecting the formation of the fascicle structure. Through cell-type specific knockdown and rescue experiments of Dscam1, we have determined that the interaction between MN24 and Scp2-positive fascicle, mediated by Dscam1, promotes the development of both dendrites and axonal routing. Our findings demonstrate that the holistic configuration of neuronal structures, such as axons and dendrites, within single motoneurons can be governed by local contact with the adjacent neuron fascicle, a novel reference structure for neural circuitry wiring.
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Background:
The identification of new cellular receptors has been increasing rapidly. A receptor is called "orphan" if an endogenous ligand has not been identified yet.
Methods:
Here we review receptors that contribute to prostate cancer and are considered orphan or partially orphan. This means that the full spectrum of their endogenous ligands remains unknown.
Results:
The orphan receptors are divided into two major families. The first group includes G protein-coupled receptors. Most are orphan olfactory receptors. OR51E1 inhibits cell proliferation and induces senescence in prostate cancer. OR51E2 inhibits prostate cancer growth, but promotes invasiveness and metastasis. GPR158, GPR110, and GPCR-X play significant roles in prostate cancer development and progression. However, GPR160 induces cell cycle arrest and apoptosis. The other major subset of orphan receptors are nuclear receptors. Receptor-related orphan receptor α (RORα) inhibits tumor growth, but RORγ stimulates androgen receptor signaling. PXR contributes to metabolic deactivation of androgens and inhibits cell proliferation. TLX has protumorigenic effects in prostate cancer, while its knockdown triggers cellular senescence and growth arrest. Estrogen-related receptor ERRγ can inhibit tumor growth but ERRα is protumorigenic. Dax1 and short heterodimeric partner are also inhibitory in prostate cancer.
Conclusion:
There is a "zoo" of relatively underappreciated orphan receptors that play key roles in prostate cancer.
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