Subepithelial Network Research Articles

A peripheral subepithelial network for chemotactile processing in the predatory sea slug Pleurobranchaea californica.

Many soft-bodied animals have extensive peripheral nervous systems (PNS) with significant sensory roles. One such, the sea slug Pleurobranchaea californica, uses PNS computations in its chemotactile oral veil (OV) in prey tracking, averaging olfactory stimuli across the OV to target likely source direction, or "stimulus place". This suggests a peripheral subepithelial network (SeN) interconnecting sensory sites to compute the directional average. We pursued anatomy and connectivity of previously described ciliated putative sensory cells on OV papillae. Scanning electron microscopy (SEM) confirmed paddle-shaped cilia in clusters. Anti-tubulin and phalloidin staining showed connections to branching nervelets and muscle fibers for contraction and expansion of papillae. Ciliary cell processes could not be traced into nerves, consistent with sensory transmission to CNS via secondary afferents. Anti-tyrosine hydroxylase-stained ciliated cells in clusters and revealed an at least partially dopaminergic subepithelial network interconnecting clusters near and distant, connections consistent with PNS averaging of multiple stimulated loci. Other, unidentified, SeN neurotransmitters are likely. Confirming chemotactile functions, perfusible suction electrodes recorded ciliary spiking excited by both mechanical and appetitive chemical stimuli. Stimuli induced sensory nerve spiking like that encoding stimulus place. Sensory nerve spikes and cilia cluster spikes were not identifiable as generated by the same neurons. Ciliary clusters likely drive the sensory nerve spikes via SeN, mediating appetitive and stimulus place codes to CNS. These observations may facilitate future analyses of the PNS in odor discrimination and memory, and also suggest such SeNs as potential evolutionary precursors of CNS place-coding circuitry in the segmented, skeletonized protostomes and deuterostomes.

Wet surface wall model for latent heat exchange during evaporation.

Air conditioning is a dual heat and mass transfer process, and the human nasal cavity achieves this through the mucosal wall surface, which is supplied with an energy source through the sub‐epithelial network of capillaries. Computational studies of air conditioning in the nasal cavity have included temperature and humidity, but most studies solved these flow parameters separately, and in some cases, a constant mucosal surface temperature was used. Recent developments demonstrated that both heat and mass transfer need to be modeled. This work expands on existing modeling efforts in accounting for the nasal cavity's dual heat and mass transfer process by introducing a new subwall model, given in the Supplementary Materials. The model was applied to a pipe geometry, and a human nasal cavity was recreated from CT‐scans, and six inhalation conditions were studied. The results showed that when the energy transfer from the latent heat of evaporation is included, there is a cooling effect on the mucosal surface temperature.

Lineage Tracing of FOXL1+ Cells in the Tunica Muscularis Suggests Mutual Origin for Telocytes and Smooth Muscle Cells.

We recently identified a FOXL1+ intestinal subepithelial network of telocytes (TCs) without which epithelial stem and progenitor cells cannot proliferate and support regeneration. In addition to FOXL1 lineage cell distribution along the intestinal epithelium, we also observed their presence within the muscle layers. Here, we characterized FOXL1+ lineage cells along the muscle layers of the duodenum in order to understand their progeny and relation to interstitial Cajal cells (ICCs), smooth muscle cells (SMCs) and the previously reported PDGFRa+ TCs. Using a FOXL1-Cre transgenic line in conjunction with genetic lineage labeling using the Rosa26-mTmG allele, in which Cre-marked cells produce a membrane-targeted version of green fluorescent protein (GFP), we found that within the muscle layers FOXL1 lineage GFP+ cells had two main progeny; (i) elongated multinucleated SMA+ SMCs, intermingled in parallel or perpendicular to muscle fibers. (ii) TCs displaying small cell body with multiple cell processes, expressing PDGFRa and CD34. These findings may suggest a mutual origin for TCs and SMCs.

Development of the nervous system in the early hatching larvae of the ctenophore Mnemiopsis leidyi.

Ctenophores are descendants of an early branching basal metazoan lineage, which may have evolved neurons and muscles independently from other animals. Mnemiopsis is one of the important reference ctenophore species. However, little is known about its neuromuscular organization. Here, we mapped and tracked the development of the neural and muscular elements in the early hatching cydippid larvae, as well as adult Mnemiopsis leidyi. The overall development of the neuromuscular system in Mnemiopsis was very similar to Pleurobrachia bachei, although in Mnemiopsis the entire process occurred significantly faster. The subepithelial neural cells were observed immediately after hatching. This population consisted of a dozen of separated individual neurons with short neurites. In about 2 days, when their neurites grew significantly longer and connected to their neighbors, they began to form a canonical polygonal subepithelial network. Mesogleal neural elements prominent in all studied adult ctenophores were not detectable in Mnemiopsis larvae but were clearly labeled in closely related Lobata species Bolinopsis infundibulum. Hatched larvae also had putative mechanoreceptors with long stereocilia and approximately two dozen muscle cells. In adult Mnemiopsis, the feeding lobes and auricles contained two distinct populations of neurons and neural ensembles that were not observed in other ctenophore lineages and likely represented elaborate neuronal innovations characteristic for the clade Lobata and their lifestyles.

Live imaging of collagen deposition during skin development and repair in a collagen I – GFP fusion transgenic zebrafish line

Fibrillar collagen is a major component of many tissues but has been difficult to image in vivo using transgenic approaches because of problems associated with establishing cells and organisms that generate GFP-fusion collagens that can polymerise into functional fibrils. Here we have developed and characterised GFP and mCherry collagen-I fusion zebrafish lines with basal epidermal-specific expression. We use these lines to reveal the dynamic nature of collagen-I fibril deposition beneath the developing embryonic epidermis, as well as the repair of this collagen meshwork following wounding. Transmission electron microscope studies show that these transgenic lines faithfully reproduce the collagen ultrastructure present in wild type larval skin. During skin development we show that collagen I is deposited by basal epidermal cells initially in fine filaments that are largely randomly orientated but are subsequently aligned into a cross-hatch, orthogonal sub-epithelial network by embryonic day 4. Following skin wounding, we see that sub-epidermal collagen is re-established in the denuded domain, initially as randomly orientated wisps that subsequently become bonded to the undamaged collagen and aligned in a way that recapitulates developmental deposition of sub-epidermal collagen. Crossing our GFP-collagen line against one with tdTomato marking basal epidermal cell membranes reveals how much more rapidly wound re-epithelialisation occurs compared to the re-deposition of collagen beneath the healed epidermis. By use of other tissue specific drivers it will be possible to establish zebrafish lines to enable live imaging of collagen deposition and its remodelling in various other organs in health and disease.

Evidence for an urethro-vesical crosstalk mediated by serotonin.

To study the contribution of urethral serotonin for the urethro-vesical crosstalk METHODS: Urethane-anesthetized female rats and TPH1-/- mice underwent isovolumetric or urethral-opened cystometries during intravesical or intraurethral infusion of saline or serotonin solutions. Human and rat bladders and urethrae were immunoreacted against serotonin and neuronal markers. Serotonin concentration and TPH1 mRNA were determined in rat tissue by HPLC and qPCR. In rats, under isovolumetric conditions, intraurethral serotonin infusion, but not saline, evoked bladder contractions. This was abolished by urethral anesthesia and by treatment with serotonin receptor antagonists. Serotonin infusion into the bladder had no effect. Under urethral-opened conditions, serotonin infusion reduced the frequency and increased the amplitude of reflex voiding contractions, compared to saline infusion. TPH1-/- mice, under urethral-opened conditions, exhibited increased frequency and reduced amplitude of voiding contractions compared to WT. Serotonin concentration and TPH1 mRNA expression were higher in the urethra than in the bladder. Cells 5-HT+ were found in the human and rat urethral epithelium, close to a sub-epithelial network of cholinergic and sensory fibers, but not in the bladder. Serotonin, produced and released by urethral cells activates an urethro-vesical pathway that enhances bladder reflex contractions.

VASCULOGENESIS PECULIARITIES OF THE INTRAMURAL PART OF COMMON BILE DUCT AT AN EARLY PERIOD OF HUMAN ONTOGENESIS

Morphological investigation of the peculiarities of structure and development of blood vessels of the intramural part of common bile duct (CBD) has been carried out on 72 series of histologic sections of embryos and 62 complexes of organs of human fetuses and newborns. It has been determined that since 7th week of intrauterine development period the origins of blood supply of CBD are anastomotic branches of posterior pancreato-duodenal arcade and anterior superior pancreato-duodenal artery partially. Germs of the definite structure of blood vessels of intramural part of CBD are identified as intramuscular and subepithelial vascular networks, situated around the basis of major duodenal papilla in fetuses 82,0-170,0 mm in parietal-coccygeal length.

Apport de l’OCT de segment antérieur « en face » dans le kératocône aigu

To study the corneal morphological characteristics of acute hydrops by analyzing anterior segment optical coherence tomography (AS-OCT) "en face" images. Four patients presenting with acute hydrops were examined at different stages, respectively after 1 day, 1 week, 3 weeks and 6 months. All patients had a complete ophthalmic evaluation including "en face" AS-OCT examination. In vivo confocal microscopy (IVCM) and histological analysis of the cornea obtained after penetrating keratoplasty were also performed in one patient. The "en face" AS-OCT showed that the early edema in acute hydrops corresponded to multiple epithelial microcysts associated with large intra-stromal lacunae. We also observed that, in association with the disappearance of the microcysts and lacunae, "en face" OCT demonstrated subepithelial scars in the form of weakly reflective, fine, interlaced linear opacities. These opacities subsequently increased in thickness resulting in a dense subepithelial network. These findings were consistent with the results of histological and IVCM studies. "En face" AS-OCT allows for precise study of the tissue changes occurring in acute corneal hydrops. Besides a better understanding of this rare complication of keratoconus, this new imaging technique may help clinicians to identify the corneal structural changes, which place keratoconus patients at risk of corneal hydrops.

Morphological characterization of sprouting and intussusceptive angiogenesis by SEM in oral squamous cell carcinoma

The word angiogenesis indicates the formation of new vascular segments from existing vessels such as capillaries and venules. Blood vessel formation in tumors is the result of rapid, disorganized vascular growth through two distinct mechanisms: sprouting and intussusceptive angiogenesis. The objective of this study was to elucidate the morphological aspects of these two vascular growth mechanisms in oral squamous cell carcinoma induced in hamster buccal pouch. Eight Syrian golden hamsters had their right buccal pouch treated with DMBA 0.5% and 10% carbamide peroxide for 90 days in order to produce squamous cell carcinoma in this site. Next, buccal pouches of the animals were submitted to the vascular corrosion technique and then analyzed by scanning electron microscopy. The vascular figures of sprouts were observed in the entire vascular network of the buccal pouches, as opposed to the intussusceptive angiogenesis that was predominantly observed in the sub-epithelial network. It was possible to differentiate the figures of sprouts from artifacts by the analysis of the blind ending of these structures. Intussusceptive angiogenesis was identified by the presence of holes trespassing the lumen of the capillaries. Vascular expansion occurred through intussusceptive angiogenesis in two ways: by the fusion of the pillars to form a new capillary and, by increasing the girth of the pillar to form meshes. The method of corrosion associated with scanning electron microscopy proved to be an excellent tool to study the two types of angiogenesis in oral squamous cell carcinoma in the hamster buccal pouch.

Glomerular pathology in Alport syndrome: a molecular perspective

We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM), resulting, at maturity, in a type IV collagen GBM network comprising only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually, there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end-stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic.

Vocal Polyps: Clinical, Morphological, and Immunohistochemical Aspects

To study the clinical, morphological, and immunohistochemical characteristics of vocal polyps. Prospective and retrospective. Clinical study: 76 medical charts from patients with polyps were reviewed. Histology study: in 42 slides from surgical specimens, the following were analyzed: epithelium, basal membrane, and lamina propria. In the transmission and scanning electron microscopy (TEM and SEM) studies, eight new cases of polyps were included. An immunohistochemical study was carried out in the 42 specimens, using antibody antifibronectin, antilaminin, and anticollagen IV. Genders--43% males and 57% females; age range--between 21 and 40 years (36.85%); and between 41 and 60 years of age (51.31%); smoking and drinking-reported by 39 and 15 patients, respectively; associated symptoms-vocal abuse (61%), gastroesophageal (47%), and nasosinusal symptoms (32%); occupation--teachers (24.0%) and maids (18.0%). Histology--epithelial hyperplasia (31.71%), hyperkeratosis, (14.28%), edema (100%), vessel proliferation (92.86%), and congestion (83.33%). SEM--reduction in mucous lacing and increase in desquamating cells. TEM--hyperplastic epithelium, enlargement of the intercellular junctions, dense subepithelial network of collagen and basal membrane with adhesion loss. Immunohistochemistry--greater immunoexpression of fibronectin, laminin, and collagen IV around the vessels. In vocal polyps, the morphological analyses show lamina propria with edema, vessel proliferation and inflammation, basement membrane with adhesion loss in some areas and dense network of subepithelial collagen. Immunohistochemistry techniques identify pigmentation of the antibodies anti-fibronectin, anti-laminin, and anti-collagen IV in the endothelium of blood vessels.

3P205 小腸絨毛における上皮下線維芽細胞を介したSubstancePによる情報伝達(細胞生物的課題(接着,運動骨格,伝達,膜),第48回日本生物物理学会年会)

3P205 小腸絨毛における上皮下線維芽細胞を介したSubstancePによる情報伝達(細胞生物的課題(接着,運動骨格,伝達,膜),第48回日本生物物理学会年会)

Role of Early-Life Environmental Influences in the Development of Asthma. How Painful Is It When You Catch a Bad Cold Too Early?

A number of studies have implicated lower respiratory tract viral infections early in life as a risk factor for the subsequent development of asthma. Despite extensive research, the precise molecular mechanisms and pathways by which virus infection causes airway inflammation and affects long-term control of airway function subsequent to the initial insult remain unclear. Compromised epithelial integrity, the elaboration of local pro-inflammatory mediators, and dysfunction of neural pathways may all influence airway responses to environmental stimuli. Our research has provided evidence that combined neuroimmune interactions primed by the virus can initiate and propagate a cascade of events leading to recurrent cycles of airway inflammation and obstruction. Nerve growth factor, or NGF, represents an ideal link between virus-infected respiratory epithelium and the dense subepithelial network of sensory fibers. Studies show that RSV infection promotes a large increase in the expression of NGF and its receptors in the respiratory tract of rodents and humans. Changes in neurotrophin expression in the respiratory tract may coordinate a variety of interactions between sensory afferent nerves and multiple components of the immune system and inflammatory pathways, thus generating a pathophysiological link between early-life viral infections and childhood asthma. Such pathways may provide new avenues for the prevention and treatment of asthma and allergy in the near future.

Distribution of TRPV1‐ and TRPV2‐immunoreactive afferent nerve endings in rat trachea

Nociception in the trachea is important for respiratory modulation. We investigated the distribution, neurochemical characteristics, and origin of nerve endings with immunoreactivity for candidate sensor channels, TRPV1 and TRPV2, in rat trachea. In the epithelial layer, the intraepithelial nerve endings and dense subepithelial network of nerve fibers were immunoreactive for TRPV1. In contrast, TRPV2 immunoreactivity was observed mainly in nerve fibers of the tracheal submucosal layer and in several intrinsic ganglion cells in the peritracheal plexus. Double immunostaining revealed that some TRPV1-immunoreactive nerve fibers were also immunoreactive for substance P or calcitonin gene-related peptide, but neither neuropeptide colocalized with TRPV2. Injection of the retrograde tracer, fast blue, into the tracheal wall near the thoracic inlet demonstrated labeled neurons in the jugular, nodose, and dorsal root ganglia at segmental levels of C2-C8. In the jugular and nodose ganglia, 59.3% (70/118) and 10.7% (17/159), respectively, of fast blue-labeled neurons were immunoreactive for TRPV1, compared to 8.8% (8/91) and 2.6% (5/191) for TRPV2-immunoreactive. Our results indicate that TRPV1-immunoreactive nerve endings are important for tracheal nociception, and the different expression patterns of TRPV1 and TRPV2 with neuropeptides may reflect different subpopulations of sensory neurons.

Whole-mount preparation technique for the demonstration of the intramural innervation of the guinea pig ureter

Purpose Previous histological studies investigating the innervation of the urinary tract have mainly used conventional sections in which the three-dimensional structure of the intramural innervation is difficult to achieve. In contrast the whole-mount preparation technique seems to provide a method for the visualization of the mesh like neuronal networks within the urinary tract. The purpose of the study was to investigate the distribution and regional variation of the intramural innervation in whole-mount preparations of the guinea-pig upper urinary tract. Material and methods Whole-mount preparation technique was employed in the guinea-pig upper urinary tract. Enzyme immunohistochemistry was carried using primary antibodies versus Neurofilament (NF), Tyrosine Hydroxylase (TH), Choline Acetyltransferase (ChAT) and Substance P (SP). Conventional nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase and Acetylcholinesterase (AChE) histochemistry was performed. The staining was evaluated using normal brightfield, fluorescence and laser confocal microscopy. Results NF-, TH-, ChAT- and SP-immunoreactive (-IR) nerves formed two distinct neuronal plexuses in the inner longitudinal muscle layer and the outer circular muscle. Additional TH-IR and SP-IR subepithelial networks were evident. Perivascular TH-, ChAT- and SP-IR fibres were demonstrated within adventitial and muscular layers. AChE positive nerves were revealed in all layers. Moderate NADPH-diaphorase positive innervation was found in the muscular layers. Renal pelvis, upper and lower ureter showed an overall enriched intrinsic innervation compared to the middle portion of the ureter. AChE positive and NF- and TH-IR ganglia were found at the ureteropelvic border and the distal ureter. Conclusions The technique of whole-mount preparation enables detailed morphological investigations of the intramural innervation of the upper urinary tract.

Vascularization of the Fleshy Comb in the Domestic Chicken

Up to now little is known about the vascularization of the chicken fleshy comb (crista carnosa). In order to evaluate the vascularization of the crista carnosa of the cook (breed White Leghorn), corrosion casts were created by injecting Plastoid into the internal carotid as described by Schummer (1951). Specimens were investigated by stereomicroscopy and scanning electron microscopy (SEM). Generally the dermis is highly vascularized by two capillary networks, which are localized beneath the epithelium and beneath the dermal papillas. The dense subepithelial network is characterized by the presence of sinusoid vessels. In the subcutaneous plexus numerous arteriovenous anastomoses of different types occur. Additionally there are arteriovenous anastomoses between the main vessels reaching the indentations of the comb. Our results show the presence of superficial and dense capillary networks and arteriovenous anastomoses are the anatomical basis for the functions of the chicken comb in mating behaviour and thermoregulation.Reference Schummer, A. 1951: Simplified method for plastoid corrosion. Anat. Anaz. 98, 288–290.

Cell Shape-Dependent Signaling

Fibroblasts form a subepithelial network in the gastrointestinal tract. Furuya et al . propose that this fibroblast network serves as a mechanosensor for the intestine. Using subepithelial cells cultured from rat duodenum, the authors showed that these cells predominantly express P2Y 1 receptors for adenosine triphosphate (ATP) and that application of ATP to flattened cells resulted in calcium signal; pharmacological analysis was consistent with P2Y 1 receptors mediating this response. Touching the flattened cells with a thin glass rod caused an increase in intracellular calcium concentration in the touched cell, and this calcium transient propagated to surrounding cells (both those in contact with the touched cell and those not in direct contact). The cells also exhibited touch-induced contractions. Cell stretching also triggered an increase in calcium concentration and stimulated an increase in extracellular ATP that increased with increasing stretch applied. When the cells were treated with dibutyryl cyclic adenosine 3′,5′-monophosphate (dbcAMP) to increase intracellular cAMP concentrations, the cells became stellate shaped and did not respond to touch or stretch, which appeared to be due to both decreased ATP release and decreased sensitivity to ATP. To support a model describing the fibroblasts as the mechanosensors that stimulate the enteric nerves of the villi, the authors cocultured the subepithelial fibroblasts with neural NG108-15 cells and found that touching the fibroblasts induced a calcium wave in both the fibroblast and neural cells. Thus, the authors suggest that an additional role for the subepithelial fibroblast network is a mechanosensor for the intestinal villi that releases ATP, which stimulates both the fibroblast network and the nearby sensory neurons. K. Furuya, M. Sokabe, S. Furuya, Characteristics of subepithelial fibroblasts as a mechano-sensor in the intestine: Cell shape-dependent ATP release and P2Y1 signaling. J. Cell. Sci. 118 , 3289-3304 (2005). [Abstract] [Full Text]

Cyclic adenosine monophosphate and cyclic guanosine monophosphate-phosphodiesterase isoenzymes in human vagina: Relation to nitric oxide synthase isoforms and vasoactive intestinal polypeptide-containing nerves

Objectives To evaluate the distribution of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) phosphodiesterases (PDEs) in relation to nitric oxide synthase isoforms and vasoactive intestinal polypeptide (VIP) in specimens of the human vagina. Nitric oxide and VIP, mediating biologic signals through cGMP and cAMP, have been assumed to be involved in the control of vaginal smooth muscle. Methods Immunohistochemical techniques were applied to sectioned specimens of the human vaginal wall to evaluate the presence of the PDE isoenzymes 3, 4, 5, and 10 in relation to neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), and VIP. Results Immunoreactivity (IR) for cAMP-degrading PDE-4 was observed in the vaginal nonvascular smooth musculature, as well as in the wall of subepithelial arteries. VIP-IR nerves innervated the smooth muscle portion of the vaginal wall and also formed a subepithelial network. Immunoreactivity specific for PDE-5 was also registered in vascular and nonvascular vaginal smooth muscle. Immunosignals for eNOS were detected in the endothelial lining of arteries containing PDE-5-IR smooth muscle cells. These arteries were supplied by nNOS-IR nerve fibers. PDE-10-IR smooth muscle cells were located in muscle bundles of the vaginal wall. Conclusions Our study revealed immunoreactivity specific for PDE-4, PDE-5, and PDE-10 in the vascular and nonvascular smooth muscle of the vagina. Immunosignals for PDE-4 and PDE-5 were also observed in close proximity to nNOS-IR or VIP-IR nerve fibers or to eNOS-IR endothelial cells. The distribution of PDEs may indicate a role of these enzymes in the control of the function of the human vagina.

Murine respiratory tract dendritic cells: isolation, phenotyping and functional studies

Respiratory tract dendritic cells (RTDC) form a contiguous subepithelial network within the nasorespiratory tract bridging innate and acquired immunity and have been implicated in nasal mucosal tolerance induction. Discrepancies exist between isolation techniques with respect to phenotype and function of RTDC. Therefore, the aim of this study was to modify previous methods to provide a consistent isolation method whilst maintaining good cell viability and enriched cell numbers so as to facilitate further phenotype and functional studies of murine RTDC. RTDCs isolated by enzyme digestion, Percoll density gradient centrifugation and overnight GM-CSF culture followed by MACS separation retain an archetypical immature dendritic cell phenotype, characterised by MHCII low CD40 neg CD86 neg CD80 neg CD11c low cell surface expression. Splenic-derived DC (SDC) isolated conformed to a day 1 in vitro phenotype; MHCII low CD40 neg CD86 low CD80 neg CD11c low but can further mature phenotypically in vitro. Both RTDC and SDC processed and presented antigen efficiently to T cells in vitro. Using such modified isolation procedures for RTDCs, we have developed a consistent method of RTDC enrichment, which maintains the immature phenotype and functional antigen presenting capability.

Multiple sites of L-histidine decarboxylase expression in mouse suggest novel developmental functions for histamine.

Histamine mediates many types of physiologic signals in multicellular organisms. To clarify the developmental role of histamine, we have examined the developmental expression of L-histidine decarboxylase (HDC) mRNA and the production of histamine during mouse development. The predominant expression of HDC in mouse development was seen in mast cells. The HDC expression was evident from embryonal day 13 (Ed13) until birth, and the mast cells were seen in most peripheral tissues. Several novel sites with a prominent HDC mRNA expression were revealed. In the brain, the choroid plexus showed HDC expression at Ed14 and the raphe neurons at Ed15. Close to the parturition, at Ed19, the neurons in the tuberomammillary (TM) area and the ventricular neuroepithelia also displayed a clear HDC mRNA expression and histamine immunoreactivity (HA-ir). From Ed14 until birth, the olfactory and nasopharyngeal epithelia showed an intense HDC mRNA expression and HA-ir. In the olfactory epithelia, the olfactory receptor neurons (ORN) were shown to have very prominent histamine immunoreactivity. The bipolar nerve cells in the epithelium extended both to the epithelial surface and into the subepithelial layers to be collected into thick nerve bundles extending caudally toward the olfactory bulbs. Also, in the nasopharynx, an extensive subepithelial network of histamine-immunoreactive nerve fibers were seen. Furthermore, in the peripheral tissues, the degenerating mesonephros (Ed14) and the convoluted tubules in the developing kidneys (Ed15) showed HDC expression, as did the prostate gland (Ed15). In adult mouse brain, the HDC expression resembled the neuronal pattern observed in rat brain. The expression was restricted to the TM area in the ventral hypothalamus, with the main expression in the five TM subgroups called E1-E5. A distinct mouse HDC mRNA expression was also seen in the ependymal wall of the third ventricle, which has not been reported in the rat. The tissue- and cell-specific expression patterns of HDC and histamine presented in this work indicate that histamine could have cell guidance or regulatory roles in development.