Embryonic cerebrospinal fluid influence in the subependymal neurogenic niche in adult mouse hippocampus.

The adult mouse hippocampal neurogenic niche is a complex structure which is not completely understood. It has mainly been related to the Subgranular layer of the dentate gyrus; however, as a result of differential neural stem cell populations reported in the subventricular zone of the lateral ventricle and associated with the hippocampus, the possibility remains of a multifocal niche reproducing developmental stages. Here, using a set of molecular markers for neural precursors, we describe in the adult mouse brain hippocampus the existence of a disperse population of neural precursors in the Subependymal Zone, the Dentate Migratory Stream and the hilus; these display dynamic behaviour compatible with neurogenesis. This supports the idea that the adult hippocampal niche cannot be restricted to the dentate gyrus subgranular layer. In other neurogenic niches such as the Subventricular Zone, a functional periventricular dependence has been shown due to the ability to respond to embryonic cerebro-spinal fluid. In this study, we demonstrate that neural precursors from the three areas studied (Sub-ependymal Zone, Dentate Migratory Stream and hilus) are able to modify their behaviour by increasing neurogenesis in a locally differential manner. Our results are compatible with the persistence in the adult mouse hippocampus of a neurogenic niche with the same spatial structure as that seen during development and early postnatal stages.

Multidisciplinary approach to the study of large-format oil paintings.

Cultural heritage has become a keystone for comprehending our society, as it represents and reflects our origins, passions, beliefs and traditions. Furthermore, it provides fundamental information about specific temporary spaces, materials' availability, technology, artist's intention, and site weather conditions. Our aim was to develop a multidisciplinary approach with a main focus on investigating two Italian large-format paintings located in highly diverse environments such as the National Theater of Costa Rica. We monitored environmental conditions and quantified fungal aerial spores. Then, we determined regions of possible biodeterioration with the software MicroorganismPattern and used the software PigmentArrangement to elucidate the apparent colour of the paintings based on distribution and arrangement of the pigment crystals. Finally, we characterized eight genera of calcareous nannofossils found in the ground layers of the artwork. The former Men's Canteen at the National Theater of Costa Rica presented a mean air temperature of 23.5 [Formula: see text]C, a relative humidity of 72.7% and a concentration of CO[Formula: see text] of 570 ppm. The fungal aerial concentration was 1776 spores/m[Formula: see text]. The software MicroorganismPattern identified 32 sampling regions, out of which 11 were positive for microbial contamination. The software PigmentArrangement determined that the blue crystals (ultramarine pigment) had the shortest distances between themselves (29 [Formula: see text]m). Finally, the nanofossils identified enabled us to restrict the age of the material to a biostratigraphic interval ranging from Coniacian to Maastricthian ages. By using a multidisciplinary approach we were able to explore the diptych, suggest a set of minimally invasive perspectives in tropical environments to be used worldwide and obtain key information about the artist's artistic process, materials used along with better understand its state of conservation.

AMPA Receptor Function in Hypothalamic Synapses.

AMPA receptors (AMPARs) are critical for mediating glutamatergic synaptic transmission and plasticity, thus playing a major role in the molecular machinery underlying cellular substrates of memory and learning. Their expression pattern, transport and regulatory mechanisms have been extensively studied in the hippocampus, but their functional properties in other brain regions remain poorly understood. Interestingly, electrophysiological and molecular evidence has confirmed a prominent role of AMPARs in the regulation of hypothalamic function. This review summarizes the existing evidence on AMPAR-mediated transmission in the hypothalamus, where they are believed to orchestrate the role of glutamatergic transmission in autonomous, neuroendocrine function, body homeostasis, and social behavior.

Gli2-Mediated Shh Signaling Is Required for Thalamocortical Projection Guidance.

The thalamocortical projections are part of the most important higher level processing connections in the vertebrates and follow a highly ordered pathway from their origin in the thalamus to the cerebral cortex. Their functional complexities are not only due to an extremely elaborate axon guidance process but also due to activity-dependent mechanisms. Gli2 is an intermediary transcription factor in the Sonic hedgehog (Shh) pathway. During neural early development, Shh has an important role in dorsoventral patterning, diencephalic anteroposterior patterning, and many later developmental processes, such as axon guidance and cell migration. Using a Gli2 knockout mouse line, we have studied the role of Shh signaling mediated by Gli2 in the development of the thalamocortical projections during embryonic development. In wild-type brains, we have described the normal trajectory of the thalamocortical axons into the context of the prosomeric model. Then, we have compared it with the altered thalamocortical axons course in Gli2 homozygous embryos. The thalamocortical axons followed different trajectories and were misdirected to other territories probably due to alterations in the Robo/Slit signaling mechanism. In conclusion, the alteration of Gli2-mediated Shh signaling produces an erroneous specification of several territories related with the thalamocortical axons. This is translated into a huge modification in the pathfinding signaling mechanisms needed for the correct wiring of the thalamocortical axons.

Rnd3 is necessary for the correct oligodendrocyte differentiation and myelination in the central nervous system.

Rho small GTPases are proteins with key roles in the development of the central nervous system. Rnd proteins are a subfamily of Rho GTPases, characterized by their constitutive activity. Rnd3/RhoE is a member of this subfamily ubiquitously expressed in the CNS, whose specific functions during brain development are still not well defined. Since other Rho proteins have been linked to the myelination process, we study here the expression and function of Rnd3 in oligodendrocyte development. We have found that Rnd3 is expressed in a subset of oligodendrocyte precursor cells and of mature oligodendrocytes both in vivo and in vitro. We have analyzed the role of Rnd3 in myelination using mice lacking Rnd3 expression (Rnd3gt/gt mice), showing that these mice exhibit hypomyelination in the brain and a reduction in the number of mature and total oligodendrocytes in the corpus callosum and striatum. The mutants display a decreased expression of several myelin proteins and a reduction in the number of myelinated axons. In addition, myelinated axons exhibit thinner myelin sheaths. In vitro experiments using Rnd3gt/gt mutant mice showed that the differentiation of the precursor cells is altered in the absence of Rnd3 expression, suggesting that Rnd3 is directly required for the differentiation of oligodendrocytes and, in consequence, for the correct myelination of the CNS. This work shows Rnd3 as a new protein involved in oligodendrocyte maturation, opening new avenues to further study the function of Rnd3 in the development of the central nervous system and its possible involvement in demyelinating diseases.

Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons.

The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main habenular efference and constitutes a link between forebrain regions, the midbrain, and the rostral hindbrain. The proper functional organization of habenular circuitry requires complex molecular programs to control the wiring of the habenula during development. However, the mechanisms guiding the habenular axons toward their targets remain mostly unknown. Here, we demonstrate the role of the mesodiencephalic dopaminergic neurons (substantia nigra pars compacta and ventral tegmental area) as an intermediate target for the correct medial habenular axons navigation along the anteroposterior axis. These neuronal populations are distributed along the anteroposterior trajectory of these axons in the mesodiencephalic basal plate. Using in vitro and in vivo experiments, we determined that this navigation is the result of netrin 1 attraction generated by the mesodiencephalic dopaminergic neurons. This attraction is mediated by the receptor deleted in colorectal cancer (DCC), which is strongly expressed in the medial habenular axons. The increment in our knowledge on the fasciculus retroflexus trajectory guidance mechanisms opens the possibility of analyzing if its alteration in mental health patients could account for some of their symptoms.

Revealing time's secrets at the National Theatre of Costa Rica via innovative software for cultural heritage research.

Establishing affordable, efficient, accessible, innovative, and multidisciplinary methodologies to the diagnosis of the conservation state of an artwork is key to carry out appropriate strategies of conservation and consequently to the creation of modern public policies on cultural heritage. Limited access to large-format paintings is a challenge to restoration scientists seeking to obtain information quickly, in a non-destructive and non-invasive manner, and identify regions of interest. Therefore, we put forward two unique software tools based on multispectral imaging techniques, with the long-term aim to assess the artist's intentions, creative process, and colour palette. This development paves the way for a comprehensive and multidisciplinary understanding of the mysteries encompassed in each pictorial layer, through the study of their physical and chemical characteristics. We conducted the first ever study on Musas I and Musas II, two large-format paintings by Italian artist Carlo Ferrario, located in the National Theatre of Costa Rica. In this study, we used our novel imaging techniques to choose regions of interest in order to study sample layers; while also assessing the works' state of conservation and possible biodeterioration. We explored the applications of our two versatile software tools, RegionOfInterest and CrystalDistribution, and confirmed paint stratigraphies by means of microscopy and spectroscopy analyses (OM, SEM-EDX, Fluorescent microscopy, FTIR-ATR and micro-Raman). In a pilot study, we identified the artist's main colour palette: zinc white, lead white, chrome yellow, lead read, viridian, along with artificial vermilion and ultramarine pigments. We were able to identify artificial vermilion and ultramarine and distinguish them from the natural pigments using CrystalDistribution to map the average size and diameter of the pigment crystals within the paint layers. This study demonstrated that software-based multidisciplinary imaging techniques are novel in establishing preventive and non-invasive methods for historical painting conservation studies, in addition, this study provides tools with great potential to be used in the future in applications such as virtual restoration.

Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold.

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence. This role is independent of RND3 and ARHGAP35 expression in corticospinal neurons, where they regulate dendritic spine formation, axon elongation, and pontine midline crossing in a FEZF2-dependent manner. The prevalence of neural stem cell scaffolds and their expression of RND3 and ARHGAP35 suggests that these observations might be broadly relevant for axon guidance and neural circuit formation.

Identification of B cell recognized linear epitopes in a snake venom serine proteinase from the central American bushmaster Lachesis stenophrys.

Snake venom serine proteinases are toxins that perturb hemostasis acting on proteins from the blood coagulation cascade, the fibrinolytic or the kallikrein-kinin system. Despite the relevance of these enzymes in envenomations by viper bites, the characterization of the antibody response to these toxins at the molecular level has not been previously addressed. In this work surface-located B cell recognized linear epitopes from a Lachesis stenophrys venom serine proteinase (UniProt accession number Q072L7) were predicted using an artificial neuronal network at the ABCpred server, the corresponding peptides were synthesized and their immunoreactivity was analyzed against a panel of experimental and therapeutic antivenoms. A molecular model of the L. stenophrys enzyme was built using as a template the structure of the D. acutus Dav-PA serine proteinase (Q9I8X1), which displays the highest degree of sequence similarity to the L. stenophrys enzyme among proteins of known 3D structure, and the surface-located epitopes were identified in the protein model using iCn3D. A total of 13 peptides corresponding to the surface exposed predicted epitopes from L. stenophrys serine proteinase were synthesized and, their reactivity with a rabbit antiserum against the recombinant enzyme and a panel of antivenoms was evaluated by a capture ELISA. Some of the epitopes recognized by monospecific and polyspecific antivenoms comprise sequences overlapping motifs conserved in viper venom serine proteinases. The identification and characterization of relevant epitopes recognized by B cells in snake venom toxins may provide valuable information for the preparation of immunogens that help in the production of improved therapeutic antivenoms.

Endometrioma complicado por absceso ovárico espontáneo / Endometrioma complicated by spontaneous ovarian abscess

RESUMEN OBJETIVO: reportar un caso de endometrioma complicado con absceso ovárico, exponer y discutir los factores de riesgo asociados, con la finalidad de difundir esta rara alteración y establecer el diagnóstico oportuno. CASO CLÍNICO: paciente de 34 años de edad, que acudió a consulta al Hospital Santa Rosa de Lima (Ensenada, Baja California Norte), con antecedente de dolor pélvico crónico de 5 meses de evolución y fiebre intermitente. El tratamiento con antibiótico de amplio espectro no mostró reacción satisfactoria. El ultrasonido transvaginal del ovario derecho mostró una imagen compatible con endometrioma. Mediante laparotomía se disecó la cápsula y se drenaron múltiples adherencias tubo-ováricas. El informe histopatológico confirmó el diagnóstico de endometrioma complicado por absceso. CONCLUSIÓN: es importante conocer los factores de riesgo para definir la causa de un absceso en un endometrioma, a través de la historia clínica detallada. La sospecha y diagnóstico oportuno es trascendental para reducir la morbilidad y mortalidad de esta complicación. Cualquier mujer con endometriosis en etapa avanzada es susceptible de complicaciones, como la formación de un absceso ovárico espontáneo.

ABSTRACT OBJETIVE: To report a case of Endometrioma complicated with ovarian abscess, expose and discuss the factors of risk associated with the purpose of disseminating this rare alteration and establishing the appropriate diagnosis. CASE REPORT: A 34 year old, seen at the Santa Rosa de Lima Hospital in Ensenada, Baja California, for a history of 5 months long chronic pelvic pain with intermittent fever, under treatment with broad spectrum antibiotic with no improvement. Transvaginal ultrasound revealed a compatible image with an endometrioma on the right ovary, followed by a laparotomy, capsule dissection and release of multiple tube-ovarian adhesions. The histo-pathological report confirmed that it was an ovarian endometrioma complicated by abscess. CONCLUSION: We emphasized in the study the risk factors and define a cause of an endometrioma and the clinical history details. Prevention and a good diagnoses as a priority to reduce morbi-mortality. It is very important to know that any woman with advanced stage history of endometriosis is susceptible to complications.

[Recurrent pregnancy loss: a literature review]. / Pérdida recurrente del embarazo: revisión bibliográfica.

Background: The definition of recurrent pregnancy loss varies according different authors and consensus: the American Society for Reproductive Medicine (ASRM) defines RPL when two or more pregnancy losses occur, and the European Society of Human Reproduction and Embryology (ESHRE) defines it as three or more pregnancy losses, not necessarily intrauterine. To this day, there is no uniform approach that serves as a guide in the diagnosis and treatment of this condition; this is why, in up to 50% of the cases of RPL, it will not be possible to identify the specific etiology. Objetive: To report on the recurrent pregnancy loss, in order to harmonize concepts and suggest a diagnosis and treatment for this condition approach. Method: The search strategy included, but was not limited to keywords like: recurrent abortion, infertility, habitual abortion, primary antiphospholipid syndrome, lupus anticoagulant, anti-cardiolipin antibodies and anti B2 glycoprotein I.

Developmental guidance of the retroflex tract at its bending point involves Robo1-Slit2-mediated floor plate repulsion.

The retroflex tract contains medial habenula efferents that target the hindbrain interpeduncular complex and surrounding areas. This tract displays a singular course. Initially, habenular axons extend ventralwards in front of the pretectum until they reach the basal plate. Next, they avoid crossing the local floor plate, sharply changing course caudalwards (the retroflexion alluded by the tract name) and navigate strictly antero-posteriorly across basal pretectum, midbrain and isthmus. Once they reach rhombomere 1, the habenular axons criss-cross the floor plate several times within the interpeduncular nuclear complex as they innervate it. Here we described the timing and details of growth phenomena as these axons navigate to their target. The first dorsoventral course apparently obeys Ntn1 attraction. We checked the role of local floor plate signaling in the decision to avoid the thalamic floor plate and bend caudalwards. Analyzing the altered floor and basal plates of Gli2 knockout mice, we found a contralateral projection of most habenular axons, plus ulterior bizarre navigation rostralwards. This crossing phenotype was due to a reduced expression of Slit repulsive cues, suggesting involvement of the floor-derived Robo-Slit system in the normal guidance of this tract. Using Slit and Robo mutant mice, open neural tube and co-culture assays, we determined that Robo1-Slit2 interaction is specifically required for impeding that medial habenular axons cross the thalamic floor plate. This pathfinding mechanism is essential to establish the functionally important habenulo-interpeduncular connection.

Mesencephalic origin of the rostral Substantia nigra pars reticulata.

In embryonic development, the neurons that will constitute a heterogeneous nucleus may have distinct origins. The different components of these populations reach their final location by radial and tangential migrations. The Substantia nigra pars reticulata (SNR) presents a high level of neuronal heterogeneity. It is composed by GABAergic neurons located in the mes-diencephalic basal plate. These inhibitory neurons usually display tangential migrations and it has been already described that the caudal SNR is colonized tangentially from rhombomere 1. Our aim is to unveil the origin of the rostral SNR. We have localized a Nkx6.2 positive ventricular domain located in the alar midbrain. Nkx6.2 derivatives' fate map analysis showed mainly a rostral colonization of this GABAergic neuronal population. We confirmed the mesencephalic origin by the expression of Six3. Both transcription factors are sequentially expressed along the differentiation of these neurons. We demonstrated the origin of the rostral SNR; our data allowed us to postulate that this nucleus is composed by two neuronal populations distributed in opposite gradients with different origins, one from rhombomere 1, caudal to rostral, and the other from the midbrain, rostral to caudal. We can conclude that the SNR has multiple origins and follows complex mechanisms of specification and migration. Our results support vital information for the study of genetic modifications in these extremely complex processes that result in devastating behavioral alterations and predisposition to psychiatric diseases. Understanding the development, molecular identity and functional characteristics of these diverse neuronal populations might lead to better diagnosis and treatment of several forms of neurological and psychiatric disease.

RUNX3 gene polymorphisms and haplotypes in Mexican patients with colorectal cancer.

We analyzed a possible association between RUNX3 gene polymorphisms and haplotypes in Mexican patients with colorectal cancer (CRC). Genomic DNA samples were obtained from the peripheral blood of 176 Mexican patients with CRC at diagnosis and from 195 individuals that formed the control group. The polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Association was estimated by odds ratio (OR). The haplotypes and linkage disequilibrium were established using the Arlequin v3.5 software. We found that the RUNX3 polymorphisms analyzed were in Hardy-Weinberg equilibrium. The RUNX3 rs2236852 AA genotype and A allele showed association with CRC (OR = 0.39, 95%CI = 0.21-0.73, P < 0.01; OR = 0.65, 95%CI = 0.49-0.87, P < 0.01, respectively), while the rs6672420, rs11249206, and rs760805 polymorphisms did not show significant association with CRC. The TA haplotype (SNPs rs760805 and rs2236852) showed an increased risk for CRC (OR = 2.52, 95%CI = 1.47-4.30, P < 0.001). In conclusion, we found that the AA genotype and A allele of rs2236852 polymorphism confer a decreased CRC risk, while the TA haplotype appears to increase the risk of CRC development in Mexican patients.

Modelación y simulación de la arteria aorta a partir de datos clínicos utilizando un modelo fraccional viscoelástico y el método del elemento finito / Modeling and simulation of the aorta from clinical data using a fractional viscoelastic model and finite element method

Los modelos y simulaciones de los efectos biomecánicos presentes en la arteria aorta, le proporcionan al especialista de la salud una herramienta computacional, que puede ser empleada en la prevención y el tratamiento de las enfermedades cardiovasculares. Es por esto que en la presente investigación se desarrolla un modelo matemático con la finalidad de implementarlo en simulaciones tridimensionales digitales que permitan analizar el comportamiento mecánico de arterias. Primero se describe la metodología utilizada en la construcción de la geometría de la arteria basada en imágenes provenientes de una tomografía axial computarizada, los ensayos experimentales necesarios para la obtención de los parámetros mecánicos requeridos por el modelo y por último su orden fraccional. Con lo que se obtiene una simulación mediante elementos finitos donde se identifican las zonas de mayor concentración de esfuerzos y el campo de desplazamientos. Para poder obtener estos resultados se empleó una formulación novedosa basada en modelos viscoelásticos de orden fraccional donde además se obtuvieron, a través del módulo complejo, los valores requeridos para la simulación.

The modeling and simulation of the biomechanical effects present in the aorta, give the health specialist a computational tool that can be used in the prevention and treatment of cardiovascular diseases. For that reason on this research a mathematical model was developed in order to implement digital dimensional simulations to analyze the mechanical behavior of arteries. First, its described the methodology used in the construction of the geometry of the artery based on images from a CT scan, next the necessary experimental tests to obtain mechanical parameters required by the model and finally his fractional order. Obtaining a finite element simulation where the areas of greatest stress concentration and the displacement field are identified. To obtain these results a novel formulation based on fractional order viscoelastic models was used and the values required for simulation were obtained through the complex modulus.

Determinación de la Rigidez Arterial Empleando Simulación Computacional / Determination of Arterial Stiffness Using Computational Simulation

El incremento de la rigidez arterial está asociado con el desarrollo de enfermedades cardiovasculares, las cuales constituyen una de las principales causas de muertes en el mundo. Por este motivo el desarrollo de métodos no invasivos que permitan cuantificar la rigidez arterial ha alcanzado un gran impacto. En este trabajo se estudia el método no invasivo de medición de la velocidad de la onda del pulso de la arteria braquial al tobillo (baPWV), por sus siglas en inglés. Para estudiar este método se simularon las formas de ondas de presión en el sistema arterial empleando un modelo unidimensional, a partir de las cuales se determinaron los valores de baPWV. Estos valores fueron comparados con los calculados por otros dos métodos: cfPWV (velocidad de la onda del pulso entre la carótida y la femoral, el método estándar) y PWVteor (ecuación de Bramwell-Hill), obteniéndose correlaciones significativas, r=0.967 y r=0.9828 respectivamente. Se investigó la sensibilidad del método baPWV a la variación de la rigidez, representada por la variación de la distensibilidad y, se concluyó que el método es sensible a los cambios de rigidez que ocurren tanto en las arterias centrales como en las arterias periféricas.

The arterial stiffness increased is associated with the development of cardiovascular diseases, which constitute one of the first causes of death globally. For this reason the development of noninvasive methods to quantify arterial stiffness have had great impact. The purpose of this paper is the study of the noninvasive measurement method of brachial ankle pulse wave velocity (baPWV). To perform this study pressure waveforms in the arterial system were simulated, by using a one-dimensional model. With these pressure waveforms baPWV's values were calculated, and were compared with two others calculated methods: cfPWV (carotid-femoral PWV, gold standard method), and PWVteor (Bramwell-Hill equation). Significant correlations were obtained, r=0.967 y r=0.9828 respectively. The sensibility of the baPWV method to the stiffness change, represented for the distensibility change, was investigated, and we conclude that baPWV method is sensitive to the changes that take place in both central and peripheral arteries.

Mesencephalic basolateral domain specification is dependent on Sonic Hedgehog.

In the study of central nervous system morphogenesis, the identification of new molecular markers allows us to identify domains along the antero-posterior and dorso-ventral (DV) axes. In the past years, the alar and basal plates of the midbrain have been divided into different domains. The precise location of the alar-basal boundary is still under discussion. We have identified Barhl1, Nhlh1 and Six3 as appropriate molecular markers to the adjacent domains of this transition. The description of their expression patterns and the contribution to the different mesencephalic populations corroborated their role in the specification of these domains. We studied the influence of Sonic Hedgehog on these markers and therefore on the specification of these territories. The lack of this morphogen produced severe alterations in the expression pattern of Barhl1 and Nhlh1 with consequent misspecification of the basolateral (BL) domain. Six3 expression was apparently unaffected, however its distribution changed leading to altered basal domains. In this study we confirmed the localization of the alar-basal boundary dorsal to the BL domain and demonstrated that the development of the BL domain highly depends on Shh.

Effect of ZNF217 gene polymorphisms on colorectal cancer development in a Mexican population.

The ZNF217 gene, a potential oncogene amplified and overexpressed in several cancers including colorectal cancer (CRC), acts as a transcription factor that activates or represses target genes. The polymorphisms rs16998248 (T>A) and rs35720349 (C>T) in coronary artery disease have been associated with reduced expression of ZNF217. In this study, we analyzed the 2 polymorphisms in Mexican patients with CRC. Genotyping of rs16998248 and rs35720349 sites was performed by polymerase chain reaction-restriction fragment length polymorphism in 203 Mexican Mestizos, 101 CRC patients, and 102 healthy blood donors. Although no statistical differences regarding genotype and allele frequencies of ZNF217 polymorphisms were observed (P > 0.05), linkage disequilibrium was significant in CRC patients (r(2) = 0.39, P < 0.0001), as a result of reduced AC haplotype frequency. Thus, the AC haplotype may protect against CRC.

Red nucleus and rubrospinal tract disorganization in the absence of Pou4f1.

The red nucleus (RN) is a neuronal population that plays an important role in forelimb motor control and locomotion. Histologically it is subdivided into two subpopulations, the parvocellular RN (pRN) located in the diencephalon and the magnocellular RN (mRN) in the mesencephalon. The RN integrates signals from motor cortex and cerebellum and projects to spinal cord interneurons and motor neurons through the rubrospinal tract (RST). Pou4f1 is a transcription factor highly expressed in this nucleus that has been related to its specification. Here we profoundly analyzed consequences of Pou4f1 loss-of-function in development, maturation and axonal projection of the RN. Surprisingly, RN neurons are specified and maintained in the mutant, no cell death was detected. Nevertheless, the nucleus appeared disorganized with a strong delay in radial migration and with a wider neuronal distribution; the neurons did not form a compacted population as they do in controls, Robo1 and Slit2 were miss-expressed. Cplx1 and Npas1, expressed in the RN, are transcription factors involved in neurotransmitter release, neuronal maturation and motor function processes among others. In our mutant mice, both transcription factors are lost, suggesting an abnormal maturation of the RN. The resulting altered nucleus occupied a wider territory. Finally, we examined RST development and found that the RN neurons were able to project to the spinal cord but their axons appeared defasciculated. These data suggest that Pou4f1 is necessary for the maturation of RN neurons but not for their specification and maintenance.