NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo.

NRAGE (also known as Maged1, Dlxin) is a member of the MAGE gene family that may play a role in the neuronal apoptosis that is regulated by the p75 neurotrophin receptor (p75NTR). To test this hypothesis in vivo, we generated NRAGE knockout mice and found that NRAGE deletion caused a defect in developmental apoptosis of sympathetic neurons of the superior cervical ganglia, similar to that observed in p75NTR knockout mice. Primary sympathetic neurons derived from NRAGE knockout mice were resistant to apoptosis induced by brain-derived neurotrophic factor (BDNF), a pro-apoptotic p75NTR ligand, and NRAGE-deficient sympathetic neurons show attenuated BDNF-dependent JNK activation. Hair follicle catagen is an apoptosis-like process that is dependent on p75NTR signaling; we show that NRAGE and p75NTR show regulated co-expression in the hair follicle and that identical defects in hair follicle catagen are present in NRAGE and p75NTR knockout mice. Interestingly, NRAGE knockout mice have severe defects in motoneuron apoptosis that are not observed in p75NTR knockout animals, raising the possibility that NRAGE may facilitate apoptosis induced by receptors other than p75NTR. Together, these studies demonstrate that NRAGE plays an important role in apoptotic-signaling in vivo.

Ultraestructura del ganglio trigémino en la esquizofrenia: primeros resultados / Ultraestructure of the trigeminal ganglion in schizophrenia: first results

La posibilidad de que el ganglio trigémino constituya un primer escalón en la diseminación del virus herpes simplex hominis tipo 1 (HSV1) al sistema nervioso central es una evidencia demostrada en trabajos experimentales en animales. La proximidad anatómica del ganglio de Gasser a estructuras del sistema límbico hace de este ganglio una localización clave en la extensión de un agente infeccioso a otras estructuras vecinas especialmente en el caso del HSV1. El ganglio de Gasser constituye un reservorio de la forma latente del HSV1 en personas normales. En la esquizofrenia –donde hay déficit en la respuesta inmunológica– aumentaría más la posibilidad de que se favorezca una afectación del complejo amígdala-hipocampo por este virus. Los genes, las situaciones de estrés y los cambios hormonales de la pubertad pudieran actuar como factores desencadenantes en este proceso de interacción virus-célula nerviosa. A pesar de todos los elementos señalados no existe en la literatura médica especializada ninguna publicación en donde se refiera haber estudiado el ganglio trigémino en la esquizofrenia por técnicas ultraestructurales. En el presente trabajo se presentan los primeros resultados del estudio ultraestructural post-mortem de este ganglio en una paciente esquizofrénica paranoide fallecida por causa no infecciosa del sistema nervioso central. Los resultados obtenidos mediante técnicas inmuno-electromicroscópicas demostraron la presencia de antígeno de HSV1 en las muestras estudiadas de este ganglio, las que tenían características similares a las observadas en esquizofrénicos adultos fallecidos, en fetos de madres esquizofrénicas y en animales experimentalmente inoculados con líquido cefalorraquídeo (LCR) de pacientes esquizofrénicos.

The possibility that the trigeminal ganglia constitutes a first step in the dissemination of the herpes simplex hominis type 1 virus (HSV1) to the central nervous system is an evidence demonstrated in experimental works in animals. The anatomical vicinity of the ganglion of Gasser to structures of the limbic system makes a key localization of this ganglion in the extension of an infectious agent to other neighbouring structures especially in the case of the HSV1. The ganglion of Gasser constitutes a reservoir in the latent form of the HSV1 in normal people. In schizophrenia, –where there is deficit in the immunologic response– it would increase more the possibility of an affectation of the amygdala hippocampus complex by this virus. Genes, stress situations and the puberty hormonal changes could act as break loose factors in this process of virus nervous cell interaction. In spite of all the pointed out elements any publication exist in the specialized medical literature where refers to have studied the trigeminal ganglia in schizophrenia by ultrastructural techniques. In the present work the first results of a post-mortem ultrastructural study of this ganglion of a paranoid schizophrenic patient deceased of non central nervous system infectious cause is presented. The results obtained by means of immuno-electronmicroscopic techniques demonstrated the presence of HSV1 antigen in the studied samples of this ganglion those that had similar characteristics to those observed in dead adults schizophrenics, foetuses from schizophrenic mothers and experimental animals inoculated with cerebrospinal fluid from schizophrenic patients.

Unilateral hypoplasia of the trigeminal ganglion.

CASE REPORT: We report a case of unilateral anaesthesia of the V1 (ophthalmic) division of the trigeminal cranial nerve presenting with persistent corneal erosions and ulceration secondary to trigeminal ganglion hypoplasia. The patient had a lifelong history of unexplained left-sided ophthalmic symptoms for which numerous diagnoses were provided. Cranial nerve testing demonstrated partial trigeminal dysfunction on the left side. Further investigation eliminated viral etiologies, and subsequent magnetic resonance imaging determined that the patient had a hypo-plastic left trigeminal ganglion. COMMENTS: We present the case to alert clinicians to the possibility of this rare condition.

Rescue of NGF-deficient mice I: transgenic expression of NGF in skin rescues mice lacking endogenous NGF.

Mice lacking a functional NGF gene (ngf-/- mice) have less than one third of the normal complement of sensory neurons, few sympathetic postganglionic neurons and die shortly after birth. We report here that transgenic expression of NGF under control of the K14 keratin promoter can rescue some elements of the peripheral nervous system and restore normal growth and viability to ngf-/- mice. While hybrid transgenic-ngf-/- mice (ngfTKOs) displayed marginal rescue of trigeminal ganglion neurons, the percentage of CGRP-positive neurons was restored to normal. Restoration of CGRP-positive terminals in skin and spinal cord was also found and accompanied by recovery of behavioral responses to noxious stimuli. ngfTKO mice displayed a normal number of superior cervical ganglion neurons and recovery of sympathetic innervation of skin. These results demonstrate that substitution of a functional NGF locus by a transgene directing expression largely to skin can result in normal growth and viability. Thus, the most vital functions of NGF are not dependent on faithful recapitulation of the normal spatiotemporal pattern of gene expression.

trkA modulation of developing somatosensory neurons in oro-facial tissues: tooth pulp fibers are absent in trkA knockout mice.

To investigate the nerve growth factor requirement of developing oro-facial somatosensory afferents, we have studied the survival of sensory fibers subserving nociception, mechanoreception or proprioception in receptor tyrosine kinase (trkA) knockout mice using immunohistochemistry. trkA receptor null mutant mice lack nerve fibers in tooth pulp, including sympathetic fibers, and showed only sparse innervation of the periodontal ligament. Ruffini endings were formed definitively in the periodontal ligament of the trkA knockout mice, although calcitonin gene-related peptide- and substance P-immunoreactive fibers were reduced in number or had disappeared completely. trkA gene deletion had also no obvious effect on the formation of Meissner corpuscles in the palate. In the vibrissal follicle, however, some mechanoreceptive afferents were sensitive for trkA gene deletion, confirming a previous report [Fundin et al. (1997) Dev. Biol. 190, 94-116]. Moreover, calretinin-positive fibers innervating longitudinal lanceolate endings were completely lost in trkA knockout mice, as were the calretinin-containing parent cells in the trigeminal ganglion.These results indicate that trkA is indispensable for developing nociceptive neurons innervating oral tissues, but not for developing mechanoreceptive neurons innervating oral tissues (Ruffini endings and Meissner corpuscles), and that calretinin-containing, trkA dependent neurons in the trigeminal ganglion normally participate in mechanoreception through longitudinal lanceolate endings of the vibrissal follicle.

MR imaging of idiopathic trigeminal neuralgia: correlation with non-surgical therapy.

Magnetic resonance (MR) findings in patients with idiopathic trigeminal neuralgia were evaluated and correlated with the effectiveness of non-surgical treatments. Thirty-four patients with idiopathic trigeminal neuralgia (ITN) were examined using T1- and T2-weighted spin-echo (SE) pulse sequence techniques to evaluate their trigeminal root-entry zones and the vessels contacted prior to non-surgical treatment (retrogasserian glycerol injection, peripheral nerve block, or only oral analgesics). Vascular contact at the proximal portion of the preganglionic segment (PGS) of the trigeminal nerve and deformity of the PGS on the affected side were observed in 97% and 47% of the patients, respectively. Non-surgical treatments were curative in 12 (67%) but failed in two (11%) of the 18 patients without deformed PGS. However, among 16 patients with deformed PGS, they were curative in only six (37.5%) and failed in four (25%). Results of this study suggest that MR imaging could be useful in the clinical assessment of trigeminal neuralgia prior to instituting non-surgical treatment.

Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice.

Sensory pathways of the brain generally develop from crudely wired networks to precisely organized systems. Several studies have implicated neural activity-dependent mechanisms, including N-methyl-D-aspartate (NMDA) receptors, in this refinement process. We applied the gene targeting to the NMDAR1 gene and created a mutant mouse that lacks functional NMDA receptors. The development of whisker-related patterns in the trigeminal nuclei of the mutant mice and their normal littermates was compared. We show that in the mutant mice pathfinding, initial targeting, and crude topographic projection of trigeminal axons in the brainstem are unaffected, but that whisker-specific patches fail to form. Our results provide a direct demonstration of the involvement of the NMDA receptor in the formation of periphery-related neural patterns in the mammalian brain.

Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20.

Krox20 is a zinc finger gene expressed in rhombomeres 3 and 5 during hindbrain development in vertebrates. Mice homozygous for a targeted mutation that deletes the majority of the Krox20 genes, including the zinc finger DNA-binding domain, died shortly after birth. The primary phenotype of the homozygous mutant animals was the loss of rhombomeres 3 and 5. This resulted in fusions of the trigeminal ganglion with the facial and vestibular ganglia, and of the superior ganglia of the glossopharyngeal and vagus nerves. These fusions resulted in a disorganization of the nerve roots of these ganglia as they entered the brain stem. These data demonstrate that Krox20 plays an essential role during development of the hindbrain and associated cranial sensory ganglia in mice.

Familial trigeminal anesthesia.

Familial congenital trigeminal anesthesia as an isolated abnormality is an unusual disorder. To our knowledge, only one family has previously been reported. We report here a family with three affected members demonstrating facial anesthesia, bilateral corneal changes, and nasal septal damage secondary to self-traumatization. Magnetic resonance imaging demonstrated hypoplasia of gasserian ganglia and trigeminal nerves in the affected father of two affected sons. The pathogenesis of this disorder appears to be congenital hypoplasia of the trigeminal nerves and gasserian ganglia that is inherited in a dominant fashion.