Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome.

We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.

In utero and lactational dioxin exposure induces Sema3b and Sema3g gene expression in the developing mouse brain.

In the developing mammalian brain, neural network formation is regulated by complex signaling cascades. In utero and lactational dioxin exposure is known to induce higher brain function abnormalities and dendritic growth disruption in rodents. However, it is unclear whether perinatal dioxin exposure affects the expression of genes involved in neural network formation. Therefore, we investigated changes in gene expression in the brain regions of developing mice born to dams administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dose: 0, 0.6, or 3.0 µg/kg) on gestational day 12.5. Quantitative RT-PCR showed that TCDD exposure induced Ahrr expression in the cerebral cortex, hippocampus, and olfactory bulb of 3-day-old mice. Gene microarray analysis indicated that the mRNA expression levels of Sema3b and Sema3g, which encode proteins that are known to control axonal projections, were elevated in the olfactory bulb of TCDD-exposed mice, and the induction of these genes was observed during a 2-week postnatal period. Increased Sema3g expression was also observed in the brain but not in the kidney, liver, lung, and spleen of TCDD-exposed neonatal mice. These results indicate that the Sema3b and Sema3g genes are sensitive to brain-specific induction by dioxin exposure, which may disrupt neural network formation in the mammalian nervous system, thereby leading to abnormal higher brain function in adulthood.

Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal brain.

After birth, stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). This migration is a fundamental event controlling the proper integration of new neurons in a pre-existing synaptic network. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we show that the actin-bundling protein fascin is highly upregulated in mouse SVZ-derived migratory neuroblasts. Fascin-1ko mice display an abnormal RMS and a smaller OB. Bromodeoxyuridine labeling experiments show that lack of fascin significantly impairs neuroblast migration, but does not appear to affect cell proliferation. Moreover, fascin depletion substantially alters the polarized morphology of rat neuroblasts. Protein kinase C (PKC)-dependent phosphorylation of fascin on Ser39 regulates its actin-bundling activity. In vivo postnatal electroporation of phosphomimetic (S39D) or nonphosphorylatable (S39A) fascin variants followed by time-lapse imaging of brain slices demonstrates that the phospho-dependent modulation of fascin activity ensures efficient neuroblast migration. Finally, fluorescence lifetime imaging microscopy studies in rat neuroblasts reveal that the interaction between fascin and PKC can be modulated by cannabinoid signaling, which controls neuroblast migration in vivo. We conclude that fascin, whose upregulation appears to mark the transition to the migratory neuroblast stage, is a crucial regulator of neuroblast motility. We propose that a tightly regulated phospho/dephospho-fascin cycle modulated by extracellular signals is required for the polarized morphology and migration in neuroblasts, thus contributing to efficient neurogenesis.

Exposure to the JNK inhibitor SP600125 (anthrapyrazolone) during early zebrafish development results in morphological defects.

SP600125 (anthrapyrazolone) is a synthetic polyaromatic chemical that inhibits c-Jun N-terminal kinase (JNK) signaling by interfering with phosphorylation of c-Jun. To determine the pharmacological impact of SP600125 on zebrafish development, we incubated embryos in various concentrations of SP600125 from 18 h postfertilization (hpf) to 48 hpf. Embryos treated with 1.25 µm appeared with occasional pericardium edema. Treatment with 12.5 µm resulted in complete mortality by 120 hpf, preventing an assessment of physiological defects. Embryos treated with 5 µm exhibited slowed overall growth, a delay in hatching and numerous morphological defects such as pericardium edema, yolk sac edema, swim bladder deflation, bent vertebrae and eye and jaw malformations. Whole-mount immunohistochemical studies using an anti-acetylated ß-tubulin antibody confirmed developmental defects in the nervous system. Within the retina, fish treated with 1.25 µm showed a mild reduction of immunoreactivity. Immunoreactivity in the retina was further reduced in fish treated with 5 µm of SP600125. In these fish, eyes and olfactory organs were half the size compared with other groups. Multiple lenses were observed in 67% of these fish. A second experiment with a shorter exposure period of SP600125 (6 h) presented significantly fewer morphological defects. The treatment led to a delay in hatching, and increased incidences of swim bladder deflation and pericardium edema with increasing concentrations. In summary, SP600125 caused developmental abnormalities during zebrafish organogenesis starting at 1.25 µm and the defects were exacerbated with increasing concentrations. Our study suggests that SP600125 at 1.25 µm and beyond has devastating consequences for zebrafish development.

[Olfactory function and olfactory bulbs in patients with Kallmann syndrome].

BACKGROUND: The majority of Kallmann patients have anosmia or hyposmia. This is how the disease is diagnosed. Some of them don't have such complaints but olfactory dysfunction is diagnosed via olfactometry. Nowadays there is the lack of information about correlation between olfactometry results and subjective complaints. Correlation between olfactory bulbs size and olfactory dysfunction has been little studied. AIM: To explore olfactory bulb size and olfactory function in patients with congenital isolated hypogonadotropic hypogonadism. To correlate olfactory bulb sizes and smell test scores. MATERIALS AND METHODS: Single-centre comparative study. 34 patients were included. The main group consisted of 19 patients with hypogonadotropic (15 -with Kallmann syndrome, 4 - with normosmic hypogonadism). Olfactory bulbs MRI were provided to all the patients, olfactory test (Sniffin' Sticks Test) and molecular-genetic studies were provided in all patients with hypogonadism. Control group consisted of 15 patients who were provided with orbits MRI. Olfactory bulbs were evaluated additionally in them. RESULTS: Normal size of olfactory bulbs were only in 1 patient with hypogonadism. Olfactory bulbs height and width were significantly smaller in patients with hypogonadism in comparison with control group (p<0.01). Height median of right bulb was 1.0 mm [0.2; 1.8] in patients from the main group vs. 3.0 [2.5; 3.2] in controls, width median of right bulb was 1.0 mm [0.2; 1.9] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Height median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 3.0 [2.7; 3.2] in controls, width median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Correlation has been established between left bulb height (r=0.59) and width (r=0.67) and olfactometry results (p<0.05). 4 patients had no anosmia complaints but had olfactory dysfunction according to Sniffin' Sticks Tests. CONCLUSION: Olfactometry was able to diagnose olfactory dysfunction in 78.5% (i.e. in 15 out of 19 patients with congenital isolated hypogonadotropic hypogonadism. However, anosmia complaints had only 11 out of 19 patients. It is the first results of olfactory bulb sizes in patients with hypogonadotropic hypogonadism in Russia. Uni - or bilateral hypoor aplasia were diagnosed in 94.7% patients with hypogonadism regardless of olfactory dysfunction. Bilateral olfactory bulbs hypoplasia were the most common MRI-finding (36.8%). Unilateral hypoor aplasia was diagnosed in 31.6% patients.

Morphological changes of olfactory bulbs and grooves: initial report of supernumerary olfactory bulbs.

BACKGROUND: Observations and measurements of olfactory structures in humans have been difficult and not of common neuroradiological interest. Because of our interest in olfaction, we have studied the presence, size, and function of these structures in normal subjects and in patients with smell loss. METHODS: Magnetic resonance imaging studies of brain were performed in 220 consecutive patients in our medical center for a variety of clinical neurological investigations. Magnetic resonance imaging studies were performed in each subject including high-resolution coronal T2-weighted fast-spin echo images in the orbitofrontal region. Measurements of olfactory bulb diameter, olfactory sulcal depth, and morphology of the olfactory grooves were performed. RESULTS: Olfactory bulbs were present bilaterally in each patient studied. Olfactory bulbs appeared duplicated in 11 patients and triplicated in one (5.4% of the total group). Whereas olfactory sulcal depth was similar in all patients, olfactory bulb diameter in patients with duplicate or triplicate bulbs was significantly smaller than those in subjects with single bilateral olfactory bulbs. One patient with congenital hyposmia and olfactory bulb duplication had significant impairment in olfactory acuity. None of the other subjects complained of smell loss. CONCLUSIONS: Olfactory bulbs with a duplicated or triplicated appearance and associated changes in olfactory groove morphology can be present in patients examined with orbital magnetic resonance imaging, and are not uncommon. Although the mechanism(s) for this finding is unclear, it may relate to neurodevelopmental and genetic factors.

Expanding the clinical and neuroradiological phenotype of 6q27 microdeletion: olfactory bulb aplasia and anosmia.

Subtelomeric deletions of chromosome 6q may result in a syndrome with brain malformations, comprising hydrocephalus and hypoplasia of the corpus callosum. Aplasia of the olfactory bulbs (OB) or anosmia has not been described in this syndrome. We describe a 3-year-old girl and a 25-year-old man with subtelomere 6q deletions. Both patients had aplastic OB and hydrocephalus. Subtelomeric 6q deletions might be underdiagnosed as anosmia can be the only symptom.

Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells.

Adrenomedullin (AM) is a peptide hormone involved in the modulation of cellular growth, migration, apoptosis, and angiogenesis. These characteristics suggest that AM is involved in the control of neural stem/progenitor cell (NSPC) biology. To explore this hypothesis, we have obtained NSPC from the olfactory bulb of adult wild-type animals and brain conditional knockouts for adm, the gene that produces AM. Knockout NSPC contain higher levels of hyperpolymerized tubulin and more abundant filopodia than adm-containing cells, resulting in a different morphology in culture, whereas the size of the knockout neurospheres is smaller than that of the wild-types. Proliferation studies have demonstrated that adm-null NSPC incorporate less 5'-bromodeoxyuridine (BrdU) than their wild-type counterparts. In contrast, BrdU studies in the olfactory bulb of adult animals show more labeled cells in adm-null mice that in wild-types, suggesting that a compensatory mechanism exists that guarantees the sufficient production of neural cells in this organ. In NSPC differentiation tests, lack of adm results in significantly lower proportions of neurons and astrocytes and higher proportions of oligodendrocytes. The oligodendrocytes produced from adm-null neurospheres present an immature phenotype with fewer and shorter processes than adm-containing oligodendrocytes. Thus, AM is an important factor in regulating the proliferation and differentiation of adult NSPC and might be used to modulate stem cell renewal and fate in protocols destined to produce neural cells for regenerative therapies.

Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice.

The Drosophila pericentrin-like protein has been shown to be essential for the formation of the sensory cilia of chemosensory and mechanosensory neurons by mutant analysis in flies, while the in vivo function of pericentrin, a well-studied mammalian centrosomal protein related to microcephalic primordial dwarfism, has been unclear. To determine whether pericentrin is required for ciliogenesis in mammals, we generated and analyzed mice with a hypomorphic mutation of Pcnt encoding the mouse pericentrin. Immunofluorescence analysis demonstrated that olfactory cilia of chemosensory neurons in the nasal olfactory epithelium were malformed in the homozygous mutant mice. On the other hand, the assembly of motile and primary cilia of non-neuronal epithelial cells and the formation of sperm flagella were not affected in the Pcnt-mutant mice. The defective assembly of olfactory cilia in the mutant was apparent from birth. The mutant animals displayed reduced olfactory performance in agreement with the compromised assembly of olfactory cilia. Our findings suggest that pericentrin is essential for the assembly of chemosensory cilia of olfactory receptor neurons, but it is not globally required for cilia formation in mammals.

Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications.

BACKGROUND: The Hedgehog (Hh) pathway provides inductive signals critical for developmental patterning of the brain and face. In humans and in animal models interference with this pathway yields birth defects, among the most well-studied of which fall within the holoprosencephaly (HPE) spectrum. METHODS: Timed-pregnant C57Bl/6J mice were treated with the natural Hh signaling antagonist cyclopamine by subcutaneous infusion from gestational day (GD) 8.25 to 9.5, or with a potent cyclopamine analog, AZ75, administered by oral gavage at GD 8.5. Subsequent embryonic morphogenesis and fetal central nervous system (CNS) phenotype were respectively investigated by scanning electron microscopy and high resolution magnetic resonance imaging (MRI). RESULTS: In utero Hh signaling antagonist exposure induced a spectrum of craniofacial and brain malformations. Cyclopamine exposure caused lateral cleft lip and palate (CLP) defects attributable to embryonic deficiency of midline and lower medial nasal prominence tissue. The CLP phenotype was accompanied by olfactory bulb hypoplasia and anterior pituitary aplasia, but otherwise grossly normal brain morphology. AZ75 exposure caused alobar and semilobar HPE with associated median facial deficiencies. An intermediate phenotype of median CLP was produced infrequently by both drug administration regimens. CONCLUSIONS: The results of this study suggest that interference with Hh signaling should be considered in the CLP differential and highlight the occurrence of CNS defects that are expected to be present in a cohort of patients having CLP. This work also illustrates the utility of fetal MRI-based analyses and establishes a novel mouse model for teratogen-induced CLP.

Magnetic resonance microscopy defines ethanol-induced brain abnormalities in prenatal mice: effects of acute insult on gestational day 8.

BACKGROUND: Magnetic resonance microscopy (MRM), magnetic resonance imaging (MRI) at microscopic levels, provides unprecedented opportunities to aid in defining the full spectrum of ethanol's insult to the developing brain. This is the first in a series of reports that, collectively, will provide an MRM-based atlas of developmental stage-dependent structural brain abnormalities in a Fetal Alcohol Spectrum Disorders (FASD) mouse model. The ethanol exposure time and developmental stage examined for this report is gestational day (GD) 8 in mice, when the embryos are at early neurulation stages; stages present in humans early in the fourth week postfertilization. METHODS: For this study, pregnant C57Bl/6J mice were administered an ethanol dosage of 2.8 g/kg intraperitoneally at 8 days, 0 hour and again at 8 days, 4 hours postfertilization. On GD 17, fetuses that were selected for MRM analyses were immersion fixed in a Bouin's/Prohance solution. Control fetuses from vehicle-treated dams were stage-matched to those that were ethanol-exposed. The fetal mice were scanned ex vivo at 7.0 T and 512 x 512 x 1024 image arrays were acquired using 3-D spin warp encoding. The resulting 29 microm (isotropic) resolution images were processed using ITK-SNAP, a 3-D segmentation/visualization tool. Linear and volume measurements were determined for selected brain, head, and body regions of each specimen. Comparisons were made between control and treated fetuses, with an emphasis on determining (dis)proportionate changes in specific brain regions. RESULTS: As compared with controls, the crown-rump lengths of stage-matched ethanol-exposed GD 17 fetuses were significantly reduced, as were brain and whole body volumes. Volume reductions were notable in every brain region examined, with the exception of the pituitary and septal region, and were accompanied by increased ventricular volumes. Disproportionate regional brain volume reductions were most marked on the right side and were significant for the olfactory bulb, hippocampus, and cerebellum; the latter being the most severely affected. Additionally, the septal region and the pituitary were disproportionately large. Linear measures were consistent with those of volume. Other dysmorphologic features noted in the MR scans were choanal stenosis and optic nerve coloboma. CONCLUSIONS: This study demonstrates that exposure to ethanol occurring in mice at stages corresponding to the human fourth week postfertilization results in structural brain abnormalities that are readily identifiable at fetal stages of development. In addition to illustrating the utility of MR microscopy for analysis of an FASD mouse model, this work provides new information that confirms and extends human clinical observations. It also provides a framework for comparison of structural brain abnormalities resulting from ethanol exposure at other developmental stages and dosages.

Retronasal Olfaction Test Methods: A Systematic Review

Background: This report produces a bibliographic study of psychophysical tests proposed clinical assessments of retronasal olfaction. Aims: We review how these tests can be utilized and discuss their methodological properties. Study Design: Systematic review. Methods: We undertook a systematic literature review investigating the retronasal olfaction test methods. PubMed, the free online MEDLINE database on biomedical sciences, was searched for the period from 1984 to 2015 using the following relevant key phrases: "retronasal olfaction", "orthonasal olfaction", "olfaction disorders", and "olfaction test". For each of the selected titles cited in this study, the full manuscript was read and analyzed by each of the three authors of this paper independently before collaborative discussion for summation and analytical reporting. Two reviewers independently read the abstracts and full texts and categorised them into one of three subgroups as follow, suitable, not-suitable, and unsure. Then they cross-checked the results, and a third reviewer decided assigned the group "unsure" to either the suitable group or the not-suitable group. Fifty eight studies revealed as suitable for review by two authors whereas 13 found not suitable for review. The total amount of 60 uncertain (unsure) or differently categorized articles were further examined by the third author which resulted in 41 approvals and 19 rejections. Hence 99 approved articles passed the next step. Exclusion criteria were reviews, case reports, animal studies, and the articles of which methodology was a lack of olfaction tests. By this way excluded 69 papers, and finally, 30 original human research articles were taken as the data. Results: The study found that the three most widely used and accepted retronasal olfaction test methods are the retronasal olfaction test, the candy smell test and odorant presentation containers. All of the three psychophysical retronasal olfaction tests were combined with orthonasal tests in clinical use to examine and understand the smell function of the patient completely. There were two limitations concerning testing: "the lack concentrations and doses of test materials" and "performing measurements within the supra-threshold zone". Conclusion: The appropriate test agents and optimal concentrations for the retronasal olfaction tests remain unclear and emerge as limitations of the retronasal olfaction test technique. The first step to overcoming these limitations will probably require identification of retronasal olfaction thresholds. Once these are determined, the concept of retronasal olfaction and its testing methods may be thoroughly reviewed.

Genetic Deletion of Soluble Epoxide Hydroxylase Causes Anxiety-Like Behaviors in Mice.

Soluble epoxide hydrolase (sEH), an enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities, is expressed in regions of the brain such as the cortex, white matter, hippocampus, substantia nigra, and striatum. sEH is involved in the regulation of cerebrovascular and neuronal function upon pathological insults. However, the physiological significance of sEH and its underlying mechanism in modulating brain function are not fully understood. In this study, we investigated the role of sEH in anxiety and potential underlying mechanisms in mice. Western blot for protein phosphorylation and expression was performed. Immunohistochemical analyses and Nissl and Golgi staining were performed for histological examination. Mouse behaviors were evaluated by open field activity, elevated plus maze, classical fear conditioning, social preference test, and Morris water maze. Our results demonstrated that the expression of sEH was upregulated during postnatal development in wild-type (WT) mice. Genetic deletion of sEH (sEH-/-) in mice resulted in anxiety-like behavior and disrupted social preference. Increased olfactory bulb (OB) size and altered integrity of neurites were observed in sEH-/- mice. In addition, ablation of sEH in mice decreased protein expression of tyrosine hydroxylase and reduced dopamine production in the brain. Moreover, the level of phosphorylated calmodulin kinase II (CaMKII) and glycogen synthase kinase 3 α/ß (GSK3α/ß) was higher in sEH-/- mice than in WT mice. Collectively, these findings suggest that sEH is a key player in neurite outgrowth of neurons, OB development in the brain, and the development of anxiety-like behavior, by regulating the CaMKII-GSK3α/ß signaling pathway.

Septo-optic Dysplasia : Assessment of Associated Findings with Special Attention to the Olfactory Sulci and Tracts.

PURPOSE: Septo-optic dysplasia is a congenital disorder consisting of optic nerve hypoplasia and absent septum pellucidum. While associated anomalies have been described, olfactory sulcus and bulb-tract hypoplasia have been scantily reported and was the focus of this study. METHODS: The picture archival and communications system and radiology information system (PACS-RIS) was searched over 15 years for patients with suspected septo-optic dysplasia (n = 41) and cerebral magnetic resonance imaging (MRI). Included patients had coronal (≤3 mm), axial (≤4 mm), and sagittal (≤4 mm) imaging reviewed by two staff neuroradiologists by consensus. Both olfactory sulcus and bulb-tract hypoplasia were ascribed a grade of 0 (normal) to 3 (complete hypoplasia). Other associated congenital anomalies were recorded, if present. Incidence of anomalies were compared to age-matched and gender-matched control patients. RESULTS: Out of 41 septo-optic dysplasia patients 33 were included (mean age = 120.7 months), with 8 excluded due to isolated septum pellucidum absence (n = 5), isolated bilateral optic hypoplasia (n = 2), or inadequate imaging (n = 1). An olfactory sulcus was hypoplastic on one or both sides in 14/33 (42.4%). Olfactory bulb hypoplasia was noted in one or both tracts in 15/33 (45.4%). A significant correlation was found between degree of olfactory sulcal and bulb-tract hypoplasia (ρ = 0.528, p = 0.0009). Other anomalies were: anterior falx dysplasia (n = 16, 48.5%), incomplete hippocampal inversion (n = 14, 42.4%), polymicrogyria (n = 11, 33.3%), callosal complete or partial agenesis (n = 10, 30.3%), schizencephaly (n = 8, 24.2%), ectopic posterior pituitary (n = 6, 18.2%), and nodular heterotopia (n = 4, 12.1%). Of the age-matched control patients 10/33 (30.3%) had at least mild anterior falx hypoplasia, and 1 control patient was noted to have unilateral incomplete hippocampal inversion (IHI); none of the age-matched control patients had olfactory sulcus or bulb-tract hypoplasia. CONCLUSION: Olfactory sulcus and bulb-tract hypoplasia are fairly common in septo-optic dysplasia and can be discordant between sides. Of the other associated anomalies, anterior falx dysplasia seems to be the most common.

N-CAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid.

The mutation of N-CAM in mice produces a phenotype dominated by an undersized olfactory bulb and accumulation of precursors in the subependymal layer. We demonstrate here that this defect can be duplicated by injection of an enzyme that specifically destroys the polysialic acid (PSA) moiety associated with N-CAM. Studies of BrdU-labeled and pyknotic cells suggest that this defect reflects a decrease in the rostral migration of olfactory precursors and not a change in the proliferation or rate of death of these cells. In addition to their ectopic location, these cells had fewer growth cone-like processes oriented along the migration route. In contrast to tangential movement, radial migration of granule cells in the olfactory bulb was not affected by loss of PSA. These results support the proposed role for PSA in cell translocation, discriminate between different mechanisms of cell migration, and provide insight as to the nature of the N-CAM mutant phenotype.

Target-independent pattern specification in the olfactory epithelium.

In mammals, odors are detected by approximately 1000 different types of odorant receptors (ORs), each expressed by a fraction of neurons in the olfactory epithelium. Neurons expressing a given OR are confined to one of four spatial zones but are distributed randomly throughout that zone. In the olfactory bulb, the axons of neurons expressing different ORs synapse at different sites, giving rise to a highly organized and stereotyped information map. An important issue is whether the epithelial and bulbar maps evolve independently or are linked, for example, by retrograde influences of the bulb on the epithelium. Here we examined the onset of expression and patterning of genes encoding ORs and sensory transduction molecules during mouse embryogenesis and in mice lacking olfactory bulbs. Our results argue for an independent development of epithelial and bulbar maps and an early functional development that may be pertinent to pattern development in the olfactory bulb.

Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system.

N-CAM is abundantly expressed in the nervous system in the form of numerous structural variants with characteristic distribution patterns and functional properties. N-CAM-180, the variant having the largest cytoplasmic domain, is expressed by all neurons. The N-CAM-180-specific exon 18 has been deleted to generate homozygous mice unable to express this N-CAM form. The most conspicuous mutant phenotype was in the olfactory bulb, where granule cells were both reduced in number and disorganized. In addition, precursors of these cells were found to be accumulated at their origin in the subependymal zone at the lateral ventricle. Analysis of the mutant in this region suggests that the mutant phenotype involves a defect in cell migration, possibly through specific loss of the polysialylated form of N-CAM-180, which is expressed in the migration pathway. Subtle but distinct abnormalities also were observed in other regions of the brain.

Minigenes impart odorant receptor-specific axon guidance in the olfactory bulb.

An olfactory sensory neuron (OSN) expresses selectively one member from a repertoire of approximately 1000 odorant receptor (OR) genes and projects its axon to a specific glomerulus in the olfactory bulb. Both processes are here recapitulated by MOR23 and M71 OR minigenes, introduced into mice. Minigenes of 9 kb and as short as 2.2 kb are selectively expressed by neurons that do not coexpress the endogenous gene but coproject their axons to the same glomeruli. Deletion of a 395 bp upstream region in the MOR23 minigene abolishes expression. In this region we recognize sequence motifs conserved in many OR genes. Transgenic lines expressing the OR in ectopic epithelial zones form ectopic glomeruli, which also receive input from OSNs expressing the cognate endogenous receptor. This suggests a recruitment through homotypic interactions between OSNs expressing the same OR.

Endocrine and radiological studies in patients with molecularly confirmed CHARGE syndrome.

CONTEXT: CHARGE syndrome is a complex of congenital malformations, and CHD7 has been reported as a major gene involved in the etiology. OBJECTIVE: We performed endocrine and radiological studies to determine whether endocrinological disorders such as hypogonadotropic hypogonadism, GH deficiency, or hypothyroidism are involved and also whether olfactory bulb hypoplasia and semicircular canal aplasia are major signs in patients with molecularly confirmed CHARGE syndrome. DESIGN: Clinical features, endocrinological assessments, and radiological abnormalities in eight children (five boys and three girls) whose molecular analyses were available were evaluated among 15 children clinically diagnosed with CHARGE syndrome at our institute. RESULTS: We identified heterozygous CHD7 mutations in all patients screened for mutations. Four boys had micropenis and/or cryptorchidism. One was diagnosed with GH deficiency, and the other was diagnosed with hypothyroidism. Computed tomography findings revealed aplasia of the semicircular canals. Magnetic resonance imaging studies of the olfactory bulb region revealed abnormal olfactory sulci and bulb development in all children. CONCLUSION: We suggest that hypogonadism, GH deficiency, and hypothyroidism could be possible endocrinological defects in patients with CHD7 mutations and that olfactory bulb hypoplasia as well as semicircular canal aplasia should be considered as a major sign for CHARGE syndrome and recommend a computed tomography scan of the temporal bone and magnetic resonance imaging study of the olfactory bulb region.

The gene for X-linked Kallmann syndrome: a human neuronal migration defect.

A new gene from the distal short arm of the human X chromosome has recently been cloned and characterized. Mutations in this gene lead to the neuronal migration defect observed in Kallmann syndrome. Although there is no direct proof for the involvement of this gene in neuronal migration, significant similarities between its predicted protein product and neural adhesion molecules have been found. X-linked Kallmann syndrome represents the first example in vertebrates of a neuronal migration defect for which the gene has been isolated.