New functions of Semaphorin 3E and its receptor PlexinD1 during developing and adult hippocampal formation

The development and maturation of cortical circuits relies on the coordinated actions of long and short range axonal guidance cues. In this regard, the class 3 semaphorins and their receptors have been seen to be involved in the development and maturation of the hippocampal connections. However, although the role of most of their family members have been described, very few data about the participation of Semaphorin 3E (Sema3E) and its receptor PlexinD1 during the development and maturation of the entorhino-hippocampal (EH) connection are available. In the present study, we focused on determining their roles both during development and in adulthood. We determined a relevant role for Sema3E/PlexinD1 in the layer-specific development of the EH connection. Indeed, mice lacking Sema3E/PlexinD1 signalling showed aberrant layering of entorhinal axons in the hippocampus during embryonic and perinatal stages. In addition, absence of Sema3E/PlexinD1 signalling results in further changes in postnatal and adult hippocampal formation, such as numerous misrouted ectopic mossy fibers. More relevantly, we describe how subgranular cells express PlexinD1 and how the absence of Sema3E induces a dysregulation of the proliferation of dentate gyrus progenitors leading to the presence of ectopic cells in the molecular layer. Lastly, Sema3E mutant mice displayed increased network excitability both in the dentate gyrus and the hippocampus proper

Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration

Nuevas funciones de moléculas de remodelación vascular durante el desarrollo y modulación de la corteza cerebral de ratón

[spa] El desarrollo de los sistemas nervioso central y neurovascular ocurre de forma paralela, gracias a que ambos son capaces de responder a las mismas moléculas. Es por ello que, los conocimientos que se van adquiriendo sobre las funciones de estas moléculas en uno de los sistemas, son de gran utilidad para conocer sus funciones en el otro sistema. Es el caso de las proteínas Sema3E y ANG1, conocidas inicialmente por sus funciones como molécula de guía axonal, y como molécula angiogénica, respectivamente. No obstante, cada vez más se conoce que ambas proteínas desempeñan funciones en ambos sistemas. En la presente tesis, nos hemos centrado en estudiar las funciones de ambas proteínas durante el desarrollo de la formación hipocámpica, una estructura que interviene en procesos cognitivos como la memoria y el aprendizaje. Además, es una estructura que está arquitectónicamente muy bien organizada, donde las neuronas principales que lo forman, así como las conexiones aferentes principales (fibras entorrinales y comisurales/asociativas) y las conexiones intrínsecas más relevantes (fibras musgosas) se organizan formando una estructura laminar que ha sido usada como modelo de estudio fundamental en Neurociencias. Esta especificación axonal está altamente regulada por numerosos factores. Se conoce bastante bien las funciones desempeñadas por las semaforinas de la clase III en este proceso. No obstante, la participación de Sema3E y su receptor PlexinD1 en el desarrollo de las conexiones del hipocampo, no había sido analizada en detalle, y los resultados obtenidos hasta la fecha resultaron ser algo contradictorios. Por otro lado, el estudio de las funciones de ANG1 y sus receptores TIE2 e ITGB1, tampoco ha sido analizada en este aspecto. Respecto a Sema3E y PlexinD1, los resultados obtenidos indican que ambas se expresan en la formación hipocámpica en desarrollo, y que Sema3E repele los axones entorrinales in vitro, durante momentos claves del desarrollo de la conexión entorrino-hipocámpica. También indican que el binomio Sema3E/PlexinD1 no son necesarios para el establecimiento de la vía entorrino-hipocámpica, aunque en ausencia de cualquiera de las dos proteínas, aparecen axones ectópicos, que salen de la vía para invadir otras regiones. Tras analizar la citoarquitectura del hipocampo a nivel postnatal y en el adulto, se observa que en ausencia de Sema3E y PlexinD1, la capa granular del giro dentado presenta ondulaciones en la hoja suprapiramidal, así como células granulares ectópicas. También se observan alteraciones en las conexiones comisural/asociacional, las cuales se presentan difusas y poco definidas en la capa molecular interna; así como alteraciones en las fibras musgosas, que se presentan ectópicas, invadiendo la capa granular, y alcanzando la capa molecular interna. Por otro lado, en ausencia de Sema3E se observa un aumento en la proliferación de los precursores presentes en el giro dentado adulto, y un aumento de la excitabilidad a nivel del giro dentado e hipocampo propio. Respecto a ANG1 y sus receptores, los resultados obtenidos indican que ANG1 e ITGB1 se expresan en el parénquima neural del hipocampo en desarrollo, mientras que TIE2 solo se expresa en vasos sanguíneos presentes en el parénquima. No obstante, se ha observado que las tres proteínas se expresan en cultivos primarios hipocámpicos. También se ha observado que ANG1 promueve el crecimiento de la neurita más larga en los cultivos primarios hipocámpicos, así como el incremento de la distancia máxima alcanzada por los axones de los explantes de hipocampo.[eng] The development of the central nervous system runs in parallel to the development of the vascular system, thanks to the fact that both systems are able to answer to the same molecules, like Semaphorin3E (Sema3E) or Angiopoietin 1 (ANG1). Even though these molecules were initially known by its functions in axonal guidance, and in angiogenesis, respectively, it is known that both play important roles during the development of both systems. In the present study, we have focused in studying the functions of Sema3E and ANG1, during the development and axonal wiring of the hippocampal formation, a structure widely used in neuroscience studies due to its well-organized citoarchitecture, and due to its implication in many important cognitive functions. The results obtained in the present study have shown that (i) Sema3E and its high affinity receptor, PlexinD1, repel entorhinal axons in vitro, during critical steps of entorhino-hippocampal pathway development; and that absence of Sema3E/PlexinD1 signaling (ii) triggers the aberrant layering of entorhinal axons in the hippocampus; (iii) misorganizes mossy fibers with relevant ectopic fibers in the molecular layer of the adult dentate gyrus; (iv) triggers the appearance of a wavy organization of the suprapyramidal blade of the postnatal and adult dentate gyrus; (v) promotes an increase in dentate precursors proliferation in the adult dentate gyrus; and (vi) induces an increase in the hyperexcitability at the level of the adult dentate gyrus and hippocampus proper. On the other hand, the results have also shown that ANG1 and its receptors, TIE2 and IITGB1, are expressed in the developing hippocampus, and in primary hippocampal culture; and that ANG1 promotes neuritogenesis of primary hippocampal culture, as well as the increase of the maximum distance reached by the axons of hippocampal explants

Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration

Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration

Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration

Reelin expression in Creutzfeldt-Jakob disease and experimental models of transmissible spongiform encephalopathies

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589