scholarly journals Smad4 signaling establishes the somatosensory map of basal vomeronasal sensory neurons

2019 ◽  
Author(s):  
Ankana S. Naik ◽  
Jennifer M. Lin ◽  
Ed Zandro M. Taroc ◽  
Raghu R. Katreddi ◽  
Jesus A. Frias ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Critical Role ◽  
Vomeronasal Organ ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Neuronal Populations ◽  
Innervation Patterns ◽  
Circuit Formation ◽  
Accessory Olfactory System ◽  
Vomeronasal Sensory Neurons

SummaryThe accessory olfactory system is a unique model that can give insights on how the neurons can establish and maintain their identity, and connectivity. The vomeronasal organ (VNO) contains two distinct populations of vomeronasal sensory neurons (VSNs) each with specific innervation patterns to the accessory olfactory bulb (AOB). Though morphogenic signals are critical in defining various neuronal populations, the morphogenic signaling profiles that influence each VSN population remains unknown. Here, we found a pronounced BMP signaling gradient within the basal VSNs. By generating Smad4 conditional mutants, we disrupted canonical TGF-β/BMP signaling in maturing basal VSNs and in all mature VSNs. We show that Smad4 loss-of-function in immature basal neurons leads to a progressive loss of basal VSNs, reduced activation of the remnant basal VSNs, and aberrant glomeruli formation in posterior AOB. However, Smad4 ablation in all mature VSNs does not affect neuronal activity nor survival but causes aberrant glomeruli formation only in the posterior AOB. Our study reveals that Smad4 signaling plays a critical role in mediating development, function, and circuit formation of basal VSNs.

scholarly journals Automated quantification of vomeronasal glomeruli number, size, and color composition after immunofluorescent staining

2021 ◽  
Author(s):  
Shahab Bahreini Jangjoo ◽  
Jennifer M Lin ◽  
Farhood Etaati ◽  
Sydney Fearnley ◽  
Jean-François Cloutier ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Olfactory System ◽  
Digital Images ◽  
Critical Role ◽  
Genetic Mutation ◽  
Immunofluorescent Staining ◽  
Pixel Intensity ◽  
Main Olfactory System ◽  
Circuit Formation ◽  
Accessory Olfactory System

Abstract Glomeruli are neuropil rich regions of the main or accessory olfactory bulbs where the axons of olfactory or vomeronasal neurons and dendrites of mitral/tufted cells form synaptic connections. In the main olfactory system olfactory sensory neurons (OSNs) expressing the same receptor innervate one or two glomeruli. However, in the accessory olfactory system, vomeronasal sensory neurons (VSNs) expressing the same receptor can innervate up to 30 different glomeruli in the accessory olfactory bulb (AOB). Genetic mutation disrupting genes with a role in defining the identity/diversity of olfactory and vomeronasal neurons can alter the number and size of glomeruli. Interestingly, two cell surface molecules, Kirrel2 and Kirrel3, have been indicated as playing a critical role in the organization of axons into glomeruli in the AOB. Being able to quantify differences in glomeruli features, such as number, size or immunoreactivity for specific markers, is an important experimental approach to validate the role of specific genes in controlling neuronal connectivity and circuit formation in either control or mutant animals. Since the manual recognition and quantification of glomeruli on digital images is a challenging and time-consuming task, we generated a program in Python able to identify glomeruli in digital images and quantify their properties, such as size, number, and pixel intensity. Validation of our program indicates that our script is a fast and suitable tool for high throughput quantification of glomerular features of mouse lines with different genetic makeup.

scholarly journals Automated quantification of vomeronasal glomeruli number, size, and color composition after immunofluorescent staining

2021 ◽  
Author(s):  
Shahab Bahreini Jangjoo ◽  
Jennifer M Lin ◽  
Farhood Etaati ◽  
Sydney Fearnley ◽  
Jean-Francois Cloutier ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Olfactory System ◽  
Digital Images ◽  
Critical Role ◽  
Genetic Mutation ◽  
Immunofluorescent Staining ◽  
Pixel Intensity ◽  
Main Olfactory System ◽  
Circuit Formation ◽  
Accessory Olfactory System

Glomeruli are neuropil rich regions of the main or accessory olfactory bulbs where the axons of olfactory or vomeronasal neurons and dendrites of mitral/tufted cells form synaptic connections. In the main olfactory system olfactory sensory neurons (OSNs) expressing the same receptor innervate one or two glomeruli. However, in the accessory olfactory system, vomeronasal sensory neurons (VSNs) expressing the same receptor can innervate up to 30 different glomeruli in the accessory olfactory bulb (AOB). Genetic mutation disrupting genes with a role in defining the identity/diversity of olfactory and vomeronasal neurons can alter number and size of glomeruli. Interestingly, two cell surface molecules, Kirrel2 and Kirrel3, have been indicated to play a critical role in the organization of axons into glomeruli in the AOB. Being able to quantify differences in glomeruli features such as number, size or immunoreactivity for specific markers is an important experimental approach to validate the role of specific genes in controlling neuronal connectivity and circuit formation in control or mutant animals. Since the manual recognition and quantification of glomeruli on digital images is a challenging and time-consuming task, we generated a program in Python able to identify glomeruli in digital images and quantify their properties, such as size, number, and pixel intensity. Validation of our program indicates that our script is a fast and suitable tool for high throughput quantification of glomerular features of mouse lines with different genetic makeup.

Patch-Clamp Analysis of Gene-Targeted Vomeronasal Neurons Expressing a Defined V1r or V2r Receptor: Ionic Mechanisms Underlying Persistent Firing

2007 ◽  
Vol 98 (4) ◽  
pp. 2357-2369 ◽  
Author(s):  
Kirill Ukhanov ◽  
Trese Leinders-Zufall ◽  
Frank Zufall
Keyword(s):  
Sensory Neurons ◽  
Cell Damage ◽  
Critical Role ◽  
Vomeronasal Organ ◽  
Input Resistance ◽  
Cell Types ◽  
Brain Regions ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Persistent Firing

Sensory neurons in the mouse vomeronasal organ consist of two major groups, apical and basal, that project to different brain regions, express unique sets of receptors, and serve distinct functions. Electrical properties of these two subpopulations, however, have not been systematically characterized. V1rb2-tau-GFP and V2r1b-tau-GFP tagged vomeronasal sensory neurons (VSNs) were selected as prototypical apical or basal VSNs, respectively, and their biophysical properties were analyzed in acute slices that minimized cell damage. Basal V2r1b-expressing VSNs had voltage-gated conductances, and especially Na+ (Nav) and Ca2+ (Cav) currents, that were substantially larger than those observed in apical V1rb2 VSNs, although the resting membrane potential, input resistance, and membrane capacitance were similar in both cell types. Of several types of Cav currents, T-type and L-type Cav currents contributed to action potential firing, and both currents alone were capable of generating oscillatory Ca2+ spikes. The L-type Cav current was uniquely coupled to a BK large-conductance K+ current, and interplay between these channels played a critical role in repolarizing spikes and maintaining persistent firing in VSNs. Larger Nav and Cav conductances, along with a more positive inactivation voltage of the Nav current in the V2r1b VSNs, contributed to the larger spike amplitude and higher spike frequency induced by depolarizing current in these cells compared with V1rb2 VSNs. Basal GFP-negative VSNs and V2r1b VSNs responded to prolonged depolarization with persistent, but adapting discharge that could be relevant in sensory adaptation. Collectively, these results suggest a novel mechanism for regulating and encoding neuronal activity in the accessory olfactory system.

scholarly journals Calcium-activated chloride current amplifies the response to urine in mouse vomeronasal sensory neurons

2009 ◽  
Vol 135 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Chun Yang ◽  
Rona J. Delay
Keyword(s):  
Sensory Neurons ◽  
Detection System ◽  
Reversal Potential ◽  
Vomeronasal Organ ◽  
Channel Blockers ◽  
Cl Channel ◽  
Chloride Accumulation ◽  
Perforated Patch Clamp ◽  
Whole Cell Recordings ◽  
Vomeronasal Sensory Neurons

The vomeronasal organ (VNO) is an odor detection system that mediates many pheromone-sensitive behaviors. Vomeronasal sensory neurons (VSNs), located in the VNO, are the initial site of interaction with odors/pheromones. However, how an individual VSN transduces chemical signals into electrical signals is still unresolved. Here, we show that a Ca2+-activated Cl− current contributes ∼80% of the response to urine in mouse VSNs. Using perforated patch clamp recordings with gramicidin, which leaves intracellular chloride undisrupted, we found that the urine-induced inward current (Vhold = −80 mV) was decreased in the presence of chloride channel blockers. This was confirmed using whole cell recordings and altering extracellular chloride to shift the reversal potential. Further, the urine-induced currents were eliminated when both extracellular Ca2+ and Na+ were removed. Using inside-out patches from dendritic tips, we recorded Ca2+-activated Cl− channel activity. Several candidates for this Ca2+-activated Cl− channel were detected in VNO by reverse transcription–polymerase chain reaction. In addition, a chloride cotransporter, Na+-K+-2Cl− isoform 1, was detected and found to mediate much of the chloride accumulation in VSNs. Collectively, our data demonstrate that chloride acts as a major amplifier for signal transduction in mouse VSNs. This amplification would increase the responsiveness to pheromones or odorants.

scholarly journals Sox10-dependent neural crest origin of olfactory microvillous neurons in zebrafish

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ankur Saxena ◽  
Brian N Peng ◽  
Marianne E Bronner
Keyword(s):  
Neural Crest ◽  
Sensory Neurons ◽  
Olfactory Epithelium ◽  
Cell Tracking ◽  
Function Analysis ◽  
Critical Role ◽  
Primary Source ◽  
Olfactory Sensory Neurons ◽  
Cranial Neural Crest ◽  
Loss Of Function

The sense of smell in vertebrates is detected by specialized sensory neurons derived from the peripheral nervous system. Classically, it has been presumed that the olfactory placode forms all olfactory sensory neurons. In contrast, we show that the cranial neural crest is the primary source of microvillous sensory neurons within the olfactory epithelium of zebrafish embryos. Using photoconversion-based fate mapping and live cell tracking coupled with laser ablation, we followed neural crest precursors as they migrated from the neural tube to the nasal cavity. A subset that coexpressed Sox10 protein and a neurogenin1 reporter ingressed into the olfactory epithelium and differentiated into microvillous sensory neurons. Timed loss-of-function analysis revealed a critical role for Sox10 in microvillous neurogenesis. Taken together, these findings directly demonstrate a heretofore unknown contribution of the cranial neural crest to olfactory sensory neurons in zebrafish and provide important insights into the assembly of the nascent olfactory system.

scholarly journals Mechanisms underlying pre- and postnatal development of the vomeronasal organ

2021 ◽  
Author(s):  
Raghu Ram Katreddi ◽  
Paolo E. Forni
Keyword(s):  
Sexual Behaviors ◽  
Molecular Mechanisms ◽  
Vomeronasal Organ ◽  
Formyl Peptide Receptor ◽  
Vertebrate Species ◽  
Protein Subunit ◽  
Neuronal Populations ◽  
Open Questions ◽  
Formyl Peptide ◽  
Accessory Olfactory System

AbstractThe vomeronasal organ (VNO) is sensory organ located in the ventral region of the nasal cavity in rodents. The VNO develops from the olfactory placode during the secondary invagination of olfactory pit. The embryonic vomeronasal structure appears as a neurogenic area where migratory neuronal populations like endocrine gonadotropin-releasing hormone-1 (GnRH-1) neurons form. Even though embryonic vomeronasal structures are conserved across most vertebrate species, many species including humans do not have a functional VNO after birth. The vomeronasal epithelium (VNE) of rodents is composed of two major types of vomeronasal sensory neurons (VSNs): (1) VSNs distributed in the apical VNE regions that express vomeronasal type-1 receptors (V1Rs) and the G protein subunit Gαi2, and (2) VSNs in the basal territories of the VNE that express vomeronasal type-2 receptors (V2Rs) and the G subunit Gαo. Recent studies identified a third subclass of Gαi2 and Gαo VSNs that express the formyl peptide receptor family. VSNs expressing V1Rs or V2Rs send their axons to distinct regions of the accessory olfactory bulb (AOB). Together, VNO and AOB form the accessory olfactory system (AOS), an olfactory subsystem that coordinates the social and sexual behaviors of many vertebrate species. In this review, we summarize our current understanding of cellular and molecular mechanisms that underlie VNO development. We also discuss open questions for study, which we suggest will further enhance our understanding of VNO morphogenesis at embryonic and postnatal stages.

scholarly journals MEGF8 is a modifier of BMP signaling in trigeminal sensory neurons

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Caitlin Engelhard ◽  
Sarah Sarsfield ◽  
Janna Merte ◽  
Qiang Wang ◽  
Peng Li ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Sensory Neurons ◽  
Axon Growth ◽  
Genetic Screen ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Neuron Development ◽  
Forward Genetic Screen ◽  
Morphogenetic Protein ◽  
Important Regulator

Bone morphogenetic protein (BMP) signaling has emerged as an important regulator of sensory neuron development. Using a three-generation forward genetic screen in mice we have identified Megf8 as a novel modifier of BMP4 signaling in trigeminal ganglion (TG) neurons. Loss of Megf8 disrupts axon guidance in the peripheral nervous system and leads to defects in development of the limb, heart, and left-right patterning, defects that resemble those observed in Bmp4 loss-of-function mice. Bmp4 is expressed in a pattern that defines the permissive field for the peripheral projections of TG axons and mice lacking BMP signaling in sensory neurons exhibit TG axon defects that resemble those observed in Megf8−/− embryos. Furthermore, TG axon growth is robustly inhibited by BMP4 and this inhibition is dependent on Megf8. Thus, our data suggest that Megf8 is involved in mediating BMP4 signaling and guidance of developing TG axons.

scholarly journals BMP Signaling Downstream of the Highwire E3 Ligase Sensitizes Nociceptors

2018 ◽  
Author(s):  
Ken Honjo ◽  
W. Daniel Tracey
Keyword(s):  
Chronic Pain ◽  
Signaling Pathway ◽  
Sensory Neurons ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Bmp Signaling ◽  
Sensory Transduction ◽  
Noxious Heat ◽  
Nociceptive Responses ◽  
Bmp Pathway

AbstractA comprehensive understanding of the molecular machinery important for nociception is essential to improving the treatment of pain. Here, we show that the BMP signaling pathway regulates nociception downstream of the E3 ubiquitin ligase highwire (hiw). Hiw loss of function in nociceptors caused antagonistic and pleiotropic phenotypes with simultaneous insensitivity to noxious heat but sensitized responses to optogenetic activation of nociceptors. Thus, hiw functions to both positively and negatively regulate nociceptors. We find that a sensory transduction-independent sensitization pathway was associated with BMP signaling. BMP signaling in nociceptors was up-regulated in hiw mutants, and nociceptor-specific expression of hiw rescued all nociception phenotypes including the increased BMP signaling. Blocking the transcriptional output of the BMP pathway with dominant negative Mad suppressed nociceptive hypersensitivity that was induced by interfering with hiw. The up-regulated BMP signaling phenotype in hiw genetic mutants could not be suppressed by mutation in wallenda suggesting that hiw regulates BMP in nociceptors via a wallenda independent pathway. In a newly established Ca2+ imaging preparation, we observed that up-regulated BMP signaling caused a significantly enhanced Ca2+ signal in the axon terminals of nociceptors that were stimulated by noxious heat. This response likely accounts for the nociceptive hypersensitivity induced by elevated BMP signaling in nociceptors. Finally, we showed that acute activation of BMP signaling in nociceptors was sufficient to sensitize nociceptive responses to optogenetically-triggered nociceptor activation without altering nociceptor morphology. Overall, this study demonstrates the previously unrevealed roles of the Hiw-BMP pathway in the regulation of nociception and provides the first direct evidence that up-regulated BMP signaling physiologically sensitizes responses of nociceptors and nociception behaviors.Author SummaryAlthough pain is a universally experienced sensation that has a significant impact on human lives and society, the molecular mechanisms of pain remain poorly understood. Elucidating these mechanisms is particularly important to gaining insight into the clinical development of currently incurable chronic pain diseases. Taking an advantage of the powerful genetic model organism Drosophila melanogaster (fruit flies), we unveil the Highwire-BMP signaling pathway as a novel molecular pathway that regulates the sensitivity of nociceptive sensory neurons. Highwire and the molecular components of the BMP signaling pathway are known to be widely conserved among animal phyla, from nematode worms to humans. Since abnormal sensitivity of nociceptive sensory neurons can play a critical role in the development of chronic pain conditions, a deeper understanding of the regulation of nociceptor sensitivity has the potential to advance effective therapeutic strategies to treat difficult pain conditions.

scholarly journals The transcription factor Tfap2e/AP-2ε plays a pivotal role in maintaining the identity of basal vomeronasal sensory neurons

2018 ◽  
Author(s):  
Jennifer M Lin ◽  
Ed Zandro M Taroc ◽  
Jesus A Frias ◽  
Aparna Prasad ◽  
Allison N Catizone ◽  
...  
Keyword(s):  
Transcription Factor ◽  
G Protein ◽  
Sensory Neurons ◽  
Control Cell ◽  
Neuronal Cell ◽  
Vomeronasal Organ ◽  
Cell Types ◽  
Protein Subunit ◽  
Cell Type Specific ◽  
Vomeronasal Sensory Neurons

The identity of individual neuronal cell types is defined by the expression of specific combinations of transcriptional regulators that control cell type-specific genetic programs. The epithelium of the vomeronasal organ of mice contains two major types of vomeronasal sensory neurons (VSNs): 1) the apical VSNs which express vomeronasal 1 receptors (V1r) and the G-protein subunit Gαi2 and; 2) the basal VSNs which express vomeronasal 2 receptors (V2r) and the G-protein subunit Gαo. Both cell types originate from a common pool of progenitors and eventually acquire apical or basal identity through largely unknown mechanisms. The transcription factor AP-2ε, encoded by the Tfap2e gene, plays a role in controlling the development of GABAergic interneurons in the main and accessory olfactory bulb (AOB), moreover AP-2ε has been previously described to be expressed in the VSNs. Here we show that AP-2ε is expressed in postmitotic VSNs after they commit to the basal differentiation program. Loss of AP-2ε function resulted in reduced number of basal VSNs and in an increased number of neurons expressing markers of the apical lineage. Our work suggests that AP-2ε, which is expressed in late phases of differentiation, is not needed to initiate the apical-basal differentiation dichotomy but for maintaining the basal VSNs' identity by preventing the expression of apical genes. Moreover, our data suggest that differentiated VSNs of mice retain a notable level of plasticity.

scholarly journals Conditional knockout of TMEM16A/anoctamin1 abolishes the calcium-activated chloride current in mouse vomeronasal sensory neurons

2015 ◽  
Vol 145 (4) ◽  
pp. 285-301 ◽  
Author(s):  
Asma Amjad ◽  
Andres Hernandez-Clavijo ◽  
Simone Pifferi ◽  
Devendra Kumar Maurya ◽  
Anna Boccaccio ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Functional Characterization ◽  
Vomeronasal Organ ◽  
Conditional Knockout ◽  
Channel Blockers ◽  
Whole Cell ◽  
Knock Out ◽  
Cl Channels ◽  
Inside Out ◽  
Vomeronasal Sensory Neurons

Pheromones are substances released from animals that, when detected by the vomeronasal organ of other individuals of the same species, affect their physiology and behavior. Pheromone binding to receptors on microvilli on the dendritic knobs of vomeronasal sensory neurons activates a second messenger cascade to produce an increase in intracellular Ca2+ concentration. Here, we used whole-cell and inside-out patch-clamp analysis to provide a functional characterization of currents activated by Ca2+ in isolated mouse vomeronasal sensory neurons in the absence of intracellular K+. In whole-cell recordings, the average current in 1.5 µM Ca2+ and symmetrical Cl− was −382 pA at −100 mV. Ion substitution experiments and partial blockade by commonly used Cl− channel blockers indicated that Ca2+ activates mainly anionic currents in these neurons. Recordings from inside-out patches from dendritic knobs of mouse vomeronasal sensory neurons confirmed the presence of Ca2+-activated Cl− channels in the knobs and/or microvilli. We compared the electrophysiological properties of the native currents with those mediated by heterologously expressed TMEM16A/anoctamin1 or TMEM16B/anoctamin2 Ca2+-activated Cl− channels, which are coexpressed in microvilli of mouse vomeronasal sensory neurons, and found a closer resemblance to those of TMEM16A. We used the Cre–loxP system to selectively knock out TMEM16A in cells expressing the olfactory marker protein, which is found in mature vomeronasal sensory neurons. Immunohistochemistry confirmed the specific ablation of TMEM16A in vomeronasal neurons. Ca2+-activated currents were abolished in vomeronasal sensory neurons of TMEM16A conditional knockout mice, demonstrating that TMEM16A is an essential component of Ca2+-activated Cl− currents in mouse vomeronasal sensory neurons.

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