Extracellular matrix protein anosmin-1 overexpression alters dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in a MPTP model of Parkinson’s disease

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.This research was supported by MCIN/Spanish Research Agency (AEI)/grants PID2019-105995RB-I00 (J.J.T.-A. and J.V.) and PID2019-109858RB-I00 (to F. dC.); ISCIII grants Red TerCel, RD16/0011/0025 (J.J.T.-A.), PI12/02574 (J.J.T.-A.), CP21/00106 (DG-G) and PI22/00156 (DG-G); Consejería de Innovación, Ciencia y Empresa grant CTS2739 (J.J.T.-A.), Consejería de Economía, Conocimiento, Empresas y Universidad grant US-1380891 (J.J.T.-A. and J.V.), Junta de Andalucía.Funding for open access publishing: Universidad de Sevilla/CBUA.Peer reviewe

Cajal: Lessons on brain development

In 1906, Santiago Ramón y Cajal was awarded the Nobel Prize in Physiology or Medicine in recognition of his work on the structure of the nervous system. At that time, almost all of Cajal's work was carried out using the Golgi method, a technique devised by the Italian scientist Camillo Golgi, with whom he shared this prize. Cajal introduced several modifications to the method developed by Golgi and, to avoid the problems encountered in staining myelinated neurons, part of his studies were carried out on embryos and very young animals (the >ontogenetic method>). In this way, Cajal begin to describe aspects of the development of the nervous system. Here, we review some of his wonderful discoveries (for example, the description of the axonal growth cone) from which he derived some of his main theories on the anatomy and physiology of the nervous system: the chemotactic hypothesis and the neuron doctrine. © 2007 Elsevier B.V. All rights reserved.Peer Reviewe

The Bárány-Cajal letters: the correspondence between Robert Bárány and Santiago Ramón y Cajal.

The Bárány-Cajal correspondence comprises a series of letters exchanged between Robert Bárány (1876-1936) and Santiago Ramón y Cajal (1852-1934). Cajal received the Nobel Prize in 1906 in recognition of his work on the structure of the nervous system, whereas Bárány was awarded the Nobel Prize in 1914 for his work on the physiology and pathology of the vestibular apparatus. Up to now the single known correspondence were that included in the Cajals collected letters filed in the Biblioteca Nacional de España. These were four letters from Bárány to Cajal dated between 1924-1928, along with the response from Cajal to the last Báránys letter. Most of these letters are about administrative issues related to Rafael Lorente de Nó his fellowship in Upsala. Now, we have localized an initial letter from Bárány to Cajal dated in 1913, guarded in the Fernando de Castro Archive, which is included in the UNESCO Memory of the World Register as part of the Archives of Santiago Ramón y Cajal and the Spanish Neurohistological School. We have also found two more letters in the Lorente de Nó case file preserved in the Archivo de la Residencia de Estudiantes (Madrid). The aim of this communication is to present and comment these unpublished letters

Neuregulin-1/ErbB4 signaling controls the migration of oligodendrocyte precursor cells during development

During embryonic development, the oligodendrocyte precursors (OPCs) are generated in specific oligodendrogliogenic sites within the neural tube and migrate to colonize the entire CNS. Different factors have been shown to influence the OPC migration and differentiation, including morphogens, growth factors, chemotropic molecules, and extracellular matrix proteins. Neuregulins have been shown to influence the migration of neuronal precursors as well as the movement and differentiation of Schwann cells for peripheral myelination, but their role in the motility of OPCs has not been explored. In the present study, we have used the optic nerve as an experimental model to examine the function of Nrg1 and its ErbB4 receptor in the migration of OPCs in the developing embryo. In vitro experiments revealed that Nrg1 is a potent chemoattractant for the first wave of OPCs, and that this effect is mediated via ErbB4 receptor. In contrast, OPCs colonizing the optic nerve at postnatal stages (PDGFRα +-OPCs) does not respond to Nrg1-chemoattraction. We also found that mouse embryos lacking ErbB4 display deficits in early OPC migration away from different oligodendrogliogenic regions in vivo. The present findings reveal a new role for Nrg1/ErbB4 signaling in regulating OPC migration selectively during early stages of CNS development. © 2012 Elsevier Inc..This work was supported by grants from the Spanish Ministry of Science and Innovation-MICINN (SAF2007-65845, SAF2009-07842), RD07-0060 (European Union, >Una manera de hacer Europa>) and the Government of Castilla-La Mancha (ICS06024/00, PAI08-0242-3822, G-2008-C8) to F.dC., and from MICINN (SAF2008-00770, SAF2009-08049-E and CONSOLIDER CSD2007-00023) to O.M. MCO has a predoctoral fellowship from FISCAM (MOV-2007_JI/20). A.B. has a postdoctoral contract of the >Sara Borrell> program from the FIS-ISCIII/Spanish Ministry of Health. S.P. is an I3P researcher from the Spanish Research Council (CSIC). F.dC. is an employee of the Health Service of Castilla-La Mancha (SESCAM).Peer Reviewe

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

Background This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 dia- betes and chronic kidney disease, cardiovascular disease, or both. Methods In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting\u2013enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pres- sures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, 656 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). Conclusions The addition of aliskiren to standard therapy with renin\u2013angiotensin system block- ade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, 656 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful