Expression of basic helix-loop-helix/PAS genes in the mouse suprachiasmatic nucleus

The suprachiasmatic nuclei contain a circadian clock that drives rhythmicity in physiology and behavior. In mice, mutation of the Clock gene produces abnormal circadian behavior [Vitaterna M. H. et al. (1994) Science 264, 715-725]. The Clock gene encodes a protein containing basic helix-loop-helix and PAS (PER-ARNT-SIM) domains [King D. P. et al. (1997) Cell 89, 641-653]. The PAS domain may be an important structural feature of a subset of genes involved in photoreception and circadian rhythmicity. The expression and regulation of messenger RNAs encoding eight members of the basic helix-loop-helix/PAS protein superfamily were examined by in situ hybridization. Six of the genes studied (aryl hydrocarbon receptor nuclear transporter, aryl hydrocarbon receptor nuclear transporter-2, Clock, endothelial PAS-containing protein, hypoxia-inducible factor-1alpha and steroid receptor coactivator-1) were expressed in the suprachiasmatic nucleus of adult and neonatal mice. No evidence for rhythmicity of expression was observed when comparing brains collected early in the subjective day (circadian time 3) with those collected early in subjective night (circadian time 15). Neuronal PAS-containing protein-1 messenger RNA was expressed in the suprachiasmatic nucleus of adult (but not neonatal) mice, and a low-amplitude rhythm of neuronal PAS-containing protein-1 gene expression was detected in the suprachiasmatic nucleus. Neuronal PAS-containing protein-2 messenger RNA was not detected in adult or neonatal suprachiasmatic nucleus. Exposure to light at night (30 or 180 min of light, beginning at circadian time 15) did not alter the expression of any of the genes studied. The expression of multiple members of the basic helix-loop-helix/PAS family in the suprachiasmatic nucleus suggests a rich array of potential interactions relevant to the regulation of the suprachiasmatic circadian clock.     

Cyclic AMP mediates serotonin-induced synaptic enhancement of lateral giant interneuron of the crayfish

The lateral giant (LG)-mediated escape behavior of the crayfish habituates readily on repetitive sensory stimulation. Recent studies suggested that the biogenic amines serotonin and octopamine modulate the time course of recovery and/or re-depression of the LG response after habituation. However, little is known of how serotonin and octopamine effect LG habituation and what second-messenger cascades they may activate. To investigate the effect of biogenic amines on LG habituation, serotonin and octopamine were superfused before presenting repetitive sensory stimulation. Serotonin and octopamine increased the number of stimuli needed to habituate the LG response. Their effects were mimicked by mixed application of a cAMP analogue [8-(4-chlorophenylthio)-cAMP (CPT-cAMP)] and a phosphodiesterase inhibitor [3-isobutyl-1-methylxanthine (IBMX)] but not by a cGMP analogue (8-bromoguanosine 3',5'-cyclic monophosphate). Perfusion of the adenylate cyclase inhibitor (SQ22536) abolished the effect of serotonin but not that of octopamine. To investigate the site of action of each biogenic amines in the neural circuit meditating LG escape, the effect of drugs on directly and indirectly elicited postsynaptic potentials in LG was investigated. Serotonin, octopamine, and a mixture of CPT-cAMP and IBMX increased both the direct and indirect synaptic inputs. Simultaneous application of SQ22536 abolished the effect of serotonin on both inputs but did not block the effect of octopamine. Direct injection of the cAMP analogue (Sp-isomer of adenosine-3',5'-cyclic monophosphorothioate) into LG increased both the direct and indirect inputs to LG. These results indicate that serotonin mediates an increase in cAMP levels in LG, but octopamine acts independently of cAMP and cGMP.     

Serotonin-2 receptor stimulation normalizes striatal preprotachykinin messenger RNA in an animal model of Parkinson's disease.

Dopamine and serotonin neurotransmission regulate striatal preprotachykinin messenger RNA levels. In the present study, we investigated serotonin 2A/2C receptor-mediated regulation of preprotachykinin messenger RNA expression in the rat striatum after adult dopamine depletion produced with 6-hydroxydopamine. Significant reductions (46-61% of control values) in preprotachykinin messenger RNA levels were detected by in situ hybridization in rostral, central and caudal regions of the striatum after >85% dopamine depletion. Repeated administration of the specific serotonin2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide, to dopamine-depleted rats completely reversed the reduction in preprotachykinin messenger RNA levels in rostral, central and dorsal-caudal striatal regions. In unlesioned (vehicle-injected) control animals, repeated administration of (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide did not affect preprotachykinin messenger RNA expression in rostral, central and ventral-caudal striatal regions, but decreased preprotachykinin messenger RNA levels in the dorsal-caudal striatal subregion. In addition, serotonin turnover in the dopamine-depleted rostral striatum was significantly increased by 35-45% which is consistent with serotonin hyperinnervation after 6-hydroxydopamine lesions. These data show that the decrease in striatal preprotachykinin messenger RNA after dopamine depletion can be normalized with repeated serotonin2A/2C receptor stimulation. We hypothesize that this serotonin2A/2C receptor regulation of preprotachykinin messenger RNA expression after 6-hydroxydopamine is a consequence of serotonin hyperinnervation, which may include increased striatal serotonin2A/2C receptors, induced by dopamine depletion. We also propose that the serotonin system could be pharmacologically targeted to restore the direct striatal tachykinin pathway in Parkinson's disease.     

Potential roles for BMP and Pax genes in the development of iris smooth muscle.

The embryonic optic cup generates four types of tissue: neural retina, pigmented epithelium, ciliary epithelium, and iris smooth muscle. Remarkably little attention has focused on the development of the iris smooth muscle since Lewis ([1903] J. Am. Anat. 2:405-416) described its origins from the anterior rim of the optic cup neuroepithelium. As an initial step toward understanding iris smooth muscle development, I first determined the spatial and temporal pattern of the development of the iris smooth muscle in the chick by using the HNK1 antibody, which labels developing iris smooth muscle. HNK1 labeling shows that iris smooth muscle development is correlated in time and space with the development of the ciliary epithelial folds. Second, because neural crest is the only other neural tissue that has been shown to generate smooth muscle (Le Lievre and Le Douarin [1975] J. Embryo. Exp. Morphol. 34:125-154), I sought to determine whether iris smooth muscle development shares similarities with neural crest development. Two members of the BMP superfamily, BMP4 and BMP7, which may regulate neural crest development, are highly expressed by cells at the site of iris smooth muscle generation. Third, because humans and mice that are heterozygous for Pax6 mutations have no irides (Hill et al. [1991] Nature 354:522-525; Hanson et al. [1994] Nat. Genet. 6:168-173), I determined the expression of Pax6. I also examined the expression of Pax3 in the developing anterior optic cup. The developing iris smooth muscle coexpresses Pax6 and Pax3. I suggest that some of the eye defects caused by mutations in Pax6, BMP4, and BMP7 may be due to abnormal iris smooth muscle.     

Mapping of serotonin transporter messenger RNA-containing nerve cell populations in the cat brainstem

The anatomical distribution of nerve cells populations expressing serotonin transporter messenger RNA was investigated in the cat brain by means of in situ hybridization histochemistry. Formalin fixed coronal sections were hybridized with [³⁵S]dATP 3′ end-labeled oligoprobes complementary to three nucleotide sequences taken from the human and serotonin transporter. A strong hybridization signal was found in nerve cells populations exclusively localized within the brainstem. These positive cells mainly resided in the nuclei of the raphe, especially in the nuclei of the raphe dorsalis and raphe centralis superior. A small number of labeled cells was also observed in various areas including the dorsal part of the interpeduncular nucleus, in the midbrain, and the region ventrolateral to the inferior olive, the ventral midline and around the central canal, in the medulla oblongata. Overall, these data agree with the notion that in the cat, as previously suggested in the human and in the rat brain, the serotonin membrane transporter messenger RNA is predominantly expressed in areas known to contain serotonergic cell bodies.     

Monocular deprivation decreases brain-derived neurotrophic factor immunoreactivity in the rat visual cortex

Neurotrophins play a crucial role in the development and activity-dependent plasticity of the visual cortex [Berardi N. et al. (1994) Proc. natn. Acad. Sci. U.S.A. 91, 684-688; Bonhoeffer T. (1996) Curr. Opin. Neurobiol. 6, 119-126; Cellerino A. and Maffei L. (1996) Prog. Neurobiol. 49, 53-71; Domenici L. et al. (1994) NeuroReport 5, 2041-2044; Galuske R. A. W. et al (1996) Eur. J. Neurosci. 8, 1554-1559; Katz L. C. and Shatz C. J. (1996) Science 274, 1133-1138; Maffei L. et al. (1992) J. Neurosci. 12, 4651-4662; Pizzorusso T. and Maffei L. (1996) Curr. Opin. Neurol. 9, 122-125; Thoenen H. (1995) Science 270, 593-598]. As a possible mechanism of action, it has been postulated that the activity-dependent expression of neurotrophins by cortical cells could regulate synapse stabilization during the first period of postnatal life (critical period). Indeed, brain-derived neurotrophic factor messenger RNA expression in the visual cortex is regulated by neuronal activity as well as during development [Castrén E. et al. (1992) Proc. natn. Acad. Sci. U.S.A. 89, 9444-9448]. Moreover, we showed that monocular deprivation decreases brain-derived neurotrophic factor messenger RNA levels in the visual cortex receiving input from the deprived eye [Bozzi Y. et al. (1995) Neuroscience 69, 1133-1144]. What is missing, however, is the demonstration that brain-derived neurotrophic factor protein expression follows that of brain-derived neurotrophic factor messenger RNA. The aim of the present study is to fill this important gap in order to support the hypothesis that brain-derived neurotrophic factor is fundamental in the plasticity of the visual cortex. We found that brain-derived neurotrophic factor immunoreactivity peaks during the critical period and that it is preferentially localized in layers II-III and V-VI. We also demonstrated that monocular deprivation determines a decrease of brain-derived neurotrophic factor immunoreactivity exclusively in the visual cortex contralateral to the deprived eye. Our results support the proposed role for brain-derived neurotrophic factor in the development and activity-dependent plasticity of the visual cortex [Cabelli R. J. et al. (1995) Science 267, 1662-1666].     

Population studies of polymorphisms of the serotonin transporter protein gene

The range of allele frequency variation in humans for any locus that may have functionally important genetic variation needs to be documented. Therefore, we tested two polymorphisms at the serotonin transporter protein locus (SLC6A4) in samples from seven specific populations from five continental regions. We studied the promoter polymorphism which is reported to have functional significance and to be associated with anxiety- and depression-related phenotypes [Lesch et al., 1996: Science 274:1527-1531], and the intron 2 VNTR polymorphism [Lesch et al., 1994: J Neural Transm 95:157-162]. Allele frequencies for both systems show significant global variation, and consequently so do haplotype frequencies. Linkage disequilibrium varied among the populations, being absent in some and highly significant in others. These differences further document a large potential for population stratification in association studies of either of these SLC6A4 polymorphisms.     

Differential regulation of brain-derived neurotrophic factor messenger RNA cellular expression in the adult rat visual cortex.

In this study, we report a comparative analysis of the distribution of brain-derived neurotrophic factor messenger RNA in the binocular primary visual cortex of rats analysed at the end of the critical period for monocular deprivation (postnatal day 35) and during adulthood (postnatal day 90). High-resolution non-isotopic in situ hybridization coupled with Nissl staining allowed to determine the relative number of neurons expressing brain-derived neurotrophic factor messenger RNA. In postnatal day 90 rats, the relative number of neurons positive for brain-derived neurotrophic factor messenger RNA significantly decreases in layer II/III with respect to postnatal day 35 animals, being constant in all the other cortical layers. Moreover, we demonstrate that dark rearing for 22 days, starting from postnatal day 90, determines: (i) a decrease of the overall level of brain-derived neurotrophic factor messenger RNA with a consequent reduction of labelling intensity in all cells throughout cortical layers II-VI; (ii) an increase of cell numbers expressing brain-derived neurotrophic factor messenger RNA in layers IV and V; and (iii) a decreased intensity of staining for brain-derived neurotrophic factor messenger RNA in dendrites after dark rearing. A re-exposure to light for 2 h after the period of darkness almost restores the number of brain-derived neurotrophic factor RNA-positive neurons. We conclude that the maturation of brain-derived neurotrophic factor messenger RNA in neurons of layer II/III goes beyond postnatal days 35-40, which can be considered the end of the critical period [Fagiolini M. et al. (1994) Vis. Res., 34, 709-720]. Moreover, we show that the cellular expression of brain-derived neurotrophic factor messenger RNA is regulated by light in adult rats as well as during development.     

Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples

Family-based studies performed to date provide conflicting evidence of linkage/association between autistic disorder and either the "short" [Cook et al., 1997: Mol Psychiatry 2:247-250] or the "long" [Klauck et al., 1997: Hum Mol Genet 6:2233-2238] allele of a polymorphic repeat located in the serotonin transporter (5-HTT) gene promoter region, affecting 5-HTT gene expression [Lesch et al., 1996: Science 274:1527-1531]. The present study was designed to assess linkage and linkage disequilibrium in two new ethnically distinct samples of families with primary autistic probands. The 5-HTT promoter repeat was genotyped in 54 singleton families collected in Italy and in 32 singleton and 5 multiplex families collected in the U.S.A., yielding a total sample of 98 trios. Linkage/association between 5-HTT gene promoter alleles and autistic disorder was assessed using the transmission/disequilibrium test (TDT) and the haplotype-based haplotype relative risk (HHRR). Both the Italian and the American samples, either singly or combined, displayed no evidence of linkage/association between 5-HTT gene promoter alleles and autistic disorder. Our findings do not support prominent contributions of 5-HTT gene variants to the pathogenesis of idiopathic infantile autism. Heterogeneity in pathogenetic mechanisms underlying the disease may require that linkage/association studies be targeted toward patient subgroups isolated on the basis of specific biochemical markers, such as serotonin (5-HT) blood levels. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:123-127, 2000.     

Perforant path lesion induces up-regulation of stathmin messenger RNA, but not SCG10 messenger RNA, in the adult rat hippocampus

In this study, we performed in situ hybridization analysis of the expression pattern of two growth-associated proteins, stathmin and SCG10, in the hippocampus after unilateral lesion of the perforant pathway, the main excitatory input from the entorhinal cortex to the hippocampus. Stathmin is one of the major neural-enriched cytosolic phosphoproteins and a potential target of cyclic-AMP-dependent kinases [Jin L. W. et al. (1996) Neurobiol. Aging 17, 331-341; Leighton I. A. et al. (1993) Molec. Cell Biochem. 127/128, 151-156]. Three days after the lesion, stathmin messenger RNA was up-regulated ipsilaterally in the hilus, in the granule cell layer of the dentate gyrus and in the pyramidal cell layer of the CA1 region. Simultaneously, the hilar region of the contralateral dentate gyrus showed an increased stathmin messenger RNA expression. This altered expression pattern was observed until 15 days after lesion. Stathmin messenger RNA expression returned to a normal level until 21 days after lesion in all regions analysed. SCG10, a membrane-bound neuronal growth-associated protein belonging to the SCG10/stathmin gene family, did not show any alteration of messenger RNA expression after perforant path lesion. The temporal changes of stathmin messenger RNA expression in the ipsilateral hippocampus correspond well to the process of reactive synaptogenesis. The enhanced messenger RNA expression in the hilar region of the contralateral dentate gyrus might suggest a role in neurite elongation, since this region is the origin of commissural fibres involved in the sprouting response in the deafferented hippocampus. The present study provides evidence that the induction of specific growth-associated proteins is differentially regulated in the hippocampus.     

The role of serotonin in intestinal luminal sensing and secretion

This mini-review addresses the role of the neuroendocrine substance serotonin (5-hydroxytryptamine, 5-HT) in intestinal luminal sensing and secretion. Intestinal sensory neurones are activated by several mechanisms, in particular following stimulation of 'specialized' cells in the mucosa. These specialized cells are the enteroendocrine cells, which contain a wide variety of neuroendocrine transmitters. One of these enteroendocrine cells is the enterochromaffin (EC) cell, which is present throughout the intestines and contains large amounts of serotonin, predominantly in the duodenum in humans. The EC cells act as mucosal sensory transducers and secrete serotonin in response to various physiological and pathological luminal stimuli. Following release, serotonin participates in several mucosal protecting processes, one being secretion. Serotonin stimulates active ion, mucus and fluid secretion. Epithelial 5-HT(2) receptors and neuronal 5-HT(1P), 5-HT(3) and 5-HT(4) receptors mediate the secretory effect of serotonin. A transmembrane serotonin transporter terminates epithelial serotonergic signalling. The transient receptor potential ion channel family is important for processing intestinal luminal sensory signalling. Accumulating evidence suggests a significant interaction between serotonin and one of the transient receptor potential ion channels, the capsaicin-sensitive transient receptor potential vanilloid type 1. Accordingly, EC cells, serotonergic receptors and transporter(s), and transient receptor potential vanilloid type-1 ion channels are all explored as pharmacological targets for treatment of some intestinal functional disorders.     

Expression patterns of engrailed-like proteins in the chick embryo.

The protein products of both of the identified chick engrailed-like (En) genes, chick En-1 and chick En-2, are localized in cells of the developing brain, mandibular arch, spinal cord, dermatome, and ventral limb bud ectoderm, as demonstrated by labeling with the polyclonal antiserum alpha Enhb-1 developed by Davis et al. (Development 111:281-298, 1991). A subpopulation of cephalic neural crest cells is also En-protein-positive. The monoclonal antibody 4D9 recognizes the chick En-2 gene product exclusively (Patel et al.: Cell 58:955-968, 1989; Davis et al., 1991) and colocalizes with chick En-2 mRNA in the developing head region of the chick embryo as shown by in situ hybridization (Gardner et al.: J. Neurosci. Res. 21:426-437, 1988). In the present study we examine the pattern of alpha Enhb-1 and 4D9 localization throughout the chick embryo from the first appearance of antibody (Ab)-positive cells at stage 8 (Hamburger and Hamilton: J. Morphol. 88:49-92, 1951) through stage 28 (1-5.5 days). We compare the localization patterns of the two Abs to each other, as well as to the localization of the monoclonal Ab, HNK-1, which recognizes many neural crest cells, using double- and triple-label fluorescence immunohistochemistry. Most En protein-positive cells in the path of neural crest cell migration are not HNK-1 positive. In detailed examination of alpha Enhb-1 and 4D9 localization, we find previously undetected patterns of En protein localization in the prechordal plate, hindbrain, myotome, ventral body-wall mesoderm, and extraembryonic membranes. Based upon these observations we propose: 1) that En expression in the mesoderm may be induced through interaction with En expressing cells in the neuroectoderm; 2) that En expression in the head mesenchyme is associated with somitomere 4; and 3) that En expression may be involved in epithelial-mesenchymal cell transformations.     

Differential polarization of serotonin transporters in axons versus soma-dendrites: an immunogold electron microscopy study

In spite of the conventional belief that neurotransmitter uptake occurs at the synapses, we demonstrated previously that serotonin transporters and the high-affinity uptake of serotonin were not confined to the terminals but rather occurred throughout the axons [Zhou F. C. et al. (1998) Brain Res. 805, 241-254]. In the present study, the detailed distribution of serotonin transporters over various parts of the neuron was illustrated and analysed morphometrically using a pre-embedding immunogold method with a characterized serotonin transporter antibody at the electron microscopic level. Our findings reveal a highly polarized distribution of serotonin transporters between axons and soma-dendrites in two aspects. (1) On the plasma membrane, serotonin transporter-immunogold is extremely low on soma-dendrites and synaptic junctions, but consistently dense along the axons and perisynaptic area. (2) In contrast, serotonin transporter labeling in the cytoplasm is concentrated in soma and dendrites, particularly on the membranes of rough endoplasmic reticulum, Golgi complexes and tubulovesicular structures, but low in the axoplasm. The extensive distribution of serotonin transporter along the axolemma suggests a broad range of uptake sites beyond synaptic junctions, and is consistent with the notion that the major mode of transmission for serotonin neurons is through volume (extrasynaptic) transmission. The highly polarized distribution also indicates that the major serotonin uptake sites are on axons and not on soma-dendrites.     

Neural crest and the origin of ectomesenchyme: neural fold heterogeneity suggests an alternative hypothesis.

The striking similarity between mesodermally derived fibroblasts and ectomesenchyme cells, which are thought to be derivatives of the neural crest, has long been a source of interest and controversy. In mice, the gene encoding the alpha subunit of the platelet-derived growth factor receptor (PDGFRalpha) is expressed both by mesodermally derived mesenchymal cells and by ectomesenchyme. Whole-mount immunostaining previously revealed that PDGFRalpha is present in the cephalic neural fold epithelium of early murine embryos (Takakura et al. [1997] J Histochem Cytochem 45:883-893). We now show that, within the neural fold, a sharp boundary exists between E-cadherin-expressing non-neural epithelium and the neural epithelium of the dorsal ridge. In addition, we found that cells coexpressing E-cadherin and PDGFRalpha are present in the non-neural epithelium of the neural folds. These observations raise the possibility that at least some PDGFRalpha(+) ectomesenchyme originates from the lateral non-neural domain of neural fold epithelium. This inference is consistent with previous reports (Nichols [ 1981] J Embryol Exp Morphol 64:105-120; Nichols [ 1986] Am J Anat 176:221-231) that mesenchymal cells emerge precociously from an epithelial neural fold domain resembling the primitive streak in the early embryonic epiblast. Therefore, we propose the name "metablast" for this non-neural epithelial domain to indicate that it is the site of a delayed local delamination of mesenchyme similar to involution of mesoderm during gastrulation. We further propose the testable hypothesis that neural crest and ectomesenchyme are developmentally distinct progenitor populations and that at least some ectomesenchyme is metablast-derived rather than neural crest-derived tissue. Developmental Dynamics 229:118-130, 2004.     

Effect of partial sensory deprivation on monoaminergic neuromodulators in striate cortex of adult cat

The role of monoaminergic neuromodulators in the reorganization of cortical topography following limited sensory deprivation in the adult cat was investigated. The total concentrations of dopamine, noradrenaline, serotonin and their major metabolites were measured in the visual cortex of both normal control and experimental animals using microbore high-performance liquid chromatography coupled with electrochemical detection. The experimental animals were subjected to a binocular retinal lesion corresponding to the central 10 degrees of vision and killed two weeks post-lesion. The sensory deprivation was confirmed in area 17 by measuring immediate-early gene zif-268 messenger RNA expression. Following the retinal lesion, the total concentrations of noradrenaline and dopamine were significantly higher in the non-deprived cortex of retinal lesion cats than in the deprived cortex of retinal lesion cats and the cortex of normal animals. This pattern follows the release of the excitatory neurotransmitter glutamate under the same conditions. Serotonin levels were significantly lower in the deprived cortex, and its metabolite 5-hydroxyindole-3-acetic acid was significantly higher in the non-deprived cortex than in deprived cortex and normal cortex.From these results, we suggest that the modulation of noradrenaline, dopamine and serotonin is regulated by visual afferent activity.     

Serotonin in the rabbit ileum: localization,uptake, and effect on motility

Repeated experiments to localise serotonin in the myenteric plexus of rabbit ileum failed. After preincubation in serotonin (10(-5) M), an extensive varicose fibre system was detected by immunocytochemical methods. Stained fibres left the myenteric plexus and ran to the muscle layers. Labelled cell bodies could not be found, even after pretreatment with colchicine or pargyline. Application of reserpine (10(-5) M) and fluoxetine (10(-5) M) prevented serotonin uptake. Antisera against tryptophan hydroxylase revealed a rich fibre system, including those processes that entered the tertiary plexus. These fibres were able to accumulate serotonin, but again the cell bodies could not be detected. Serotonin caused concentration-dependent contraction in the longitudinal muscle layer of the rabbit ileum. Pretreatment with tetrodotoxin strongly reduced the effect of serotonin. Preapplication of atropine caused a slight decrease of response evoked by serotonin. Combined administration of tetrodotoxin and atropine significantly reduced the responses to serotonin, but did not abolish them. At the same time, agonists of 5-HT(2) and 5-HT(4) receptors caused concentration-dependent contractions. Our studies show that: 1). Without pretreatment, serotonin cannot be detected in the myenteric plexus of rabbit ileum. 2). An extensive uptake system works in this plexus. If released from myenteric nerve fibres, serotonin may evoke contractions in indirect and direct ways. 3). There may be an extrinsic serotoninergic innervation from the mesenteric ganglia. 4). Serotonin exerts its effect through 5-HT(2) and 5-HT(4) receptors on smooth muscle cells and nerve elements.     

Transient expression of a functional serotonin transporter in Merkel cells during late gestation and early postnatal rat development

We and others have previously identified serotonin transporter mRNA throughout the trigeminal system in the whisker region, trigeminal ganglion, trigeminal nucleus and thalamic relay stations. In order to further implicate a role for the serotonin transporter in this sensory system, we have now characterized serotonin transporter gene expression and function in primary cultures from the rat snout, at several stages of gestation. In this study, we have demonstrated a transient expression of serotonin transporter mRNA in quinacrine-positive Merkel cells between embryonic day 16 and postnatal day 5. Peak levels of mRNA occurred at embryonic day 20 and postnatal day 1. Merkel cells in culture exhibited a transient, antidepressant-sensitive [3H]-serotonin uptake, which was maximal at a time in culture corresponding to embryonic day 22 (day of birth). This transient uptake of serotonin suggests a role for this monoamine during a critical time period of the developing trigeminal sensory system. Regulation of extracellular serotonin levels by transporter activity may reflect the specific formation of the merkel cell-sensory neuron complex in an analogous mechanism by which serotonin modulates synaptogenesis in the central nervous system.     

Otocephaly-midline malformation association

Otocephaly ("agnathia") is a developmental field complex with structural defects limited to the craniofacial region. Previously, two infants with otocephaly, situs inversus totalis, renal defects, and vertebral and rib abnormalities were reported by Pauli et al. [Teratology 23:85-93, 1981]. We describe a similarly affected infant male, supporting the existence of this midline malformation association. A generalized disturbance in cell migration from the primitive streak may be its pathogenesis. A search for additional patients among cases of otocephaly may establish its prevalence, patterns of associated anomalies, and cause.