Biomedical subjects

Jonas Larsson

Publications and source records attributed to Jonas Larsson.

At least 19 recordsLinked to original sources

PubMed2006

Two retinotopic visual areas in human lateral occipital cortex.

We describe two visual field maps, lateral occipital areas 1 (LO1) and 2 (LO2), in the human lateral occipital cortex between the dorsal part of visual area V3 and visual area V5/MT+. Each map contained a topographic representation of the contralateral visual hemifield. The eccentricity representations were shared with V1/V2/V3. The polar angle representation in LO1 extended from the lower vertical meridian (at the boundary with dorsal V3) through the horizontal to the upper vertical meridian (at the boundary with LO2). The polar angle representation in LO2 was the mirror-reversal of that in LO1. LO1 and LO2 overlapped with the posterior part of the object-selective lateral occipital complex and the kinetic occipital region (KO). The retinotopy and functional properties of LO1 and LO2 suggest that they correspond to two new human visual areas, which lack exact homologues in macaque visual cortex. The topography, stimulus selectivity, and anatomical location of LO1 and LO2 indicate that they integrate shape information from multiple visual submodalities in retinotopic coordinates.

Brain Mapping↗

PubMed2006

Neuron-specific TGF-beta signaling deficiency results in retinal detachment and cataracts in mice.

We generated a mouse model (cKO) with a conditional deletion of TGF-beta signaling in the retinal neurons by crossing TGF-beta receptor I (TGF-beta RI) floxed mice with nestin-Cre mice. Almost all of the newborn cKO mice had retinal detachment at the retinal pigment epithelium (RPE)/photoreceptor layer junction of the neurosensory retina (NSR). The immunostaining for chondroitin-6-sulfate showed a very weak reaction in cKO mice in contrast to intense staining in the photoreceptor layer in wild-type mice. Macroscopic cataracts, in one or both eyes, were observed in 50% of the mice by 6 months of age, starting as early as the first month after birth. The cKO mouse model demonstrates that the TGF-beta signaling deficiency in retinal cells leads to decreased levels of chondroitin sulfate proteoglycan in the retinal interphotoreceptor matrix. This in turn causes retinal detachment due to the loss of adhesion of the NSR to RPE.

Animals↗

PubMed2006

Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects.

BACKGROUND: Congenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. While TGF-beta-superfamily signaling has been strongly implicated in neural crest cell development, the detailed molecular signaling mechanisms in vivo are still poorly understood. RESULTS: We deleted the TGF-beta type I receptor Alk5 specifically in the mouse neural crest cell lineage. Failure in signaling via ALK5 leads to severe cardiovascular and pharyngeal defects, including inappropriate remodeling of pharyngeal arch arteries, abnormal aortic sac development, failure in pharyngeal organ migration and persistent truncus arteriosus. While ALK5 is not required for neural crest cell migration, our results demonstrate that it plays an important role in the survival of post-migratory cardiac neural crest cells. CONCLUSION: Our results demonstrate that ALK5-mediated signaling in neural crest cells plays an essential cell-autonomous role in the pharyngeal and cardiac outflow tract development.

Activin Receptors, Type I↗

PubMed2006

Smad7 promotes self-renewal of hematopoietic stem cells.

The Smad-signaling pathway downstream of the transforming growth factor-beta superfamily of ligands is an evolutionarily conserved signaling circuitry with critical functions in a wide variety of biologic processes. To investigate the role of this pathway in the regulation of hematopoietic stem cells (HSCs), we have blocked Smad signaling by retroviral gene transfer of the inhibitory Smad7 to murine HSCs. We report here that the self-renewal capacity of HSCs is promoted in vivo upon blocking of the entire Smad pathway, as shown by both primary and secondary bone marrow (BM) transplantations. Importantly, HSCs overexpressing Smad7 have an unperturbed differentiation capacity as evidenced by normal contribution to both lymphoid and myeloid cell lineages, suggesting that the Smad pathway regulates self-renewal independently of differentiation. Moreover, phosphorylation of Smads was inhibited in response to ligand stimulation in BM cells, thus verifying impairment of the Smad-signaling cascade in Smad7-overexpressing cells. Taken together, these data reveal an important and previously unappreciated role for the Smad-signaling pathway in the regulation of self-renewal of HSCs in vivo.

Animals↗

PubMed2006

Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.

Transforming growth factor beta (TGF-beta) proteins play important roles in morphogenesis of many craniofacial tissues; however, detailed biological mechanisms of TGF-beta action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-beta type II receptor (TGFbetaRII), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and Alk5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-beta, and (2) ALK5 acts also in conjunction with type II receptors other than TGFbetaRII.

Activin Receptors, Type I↗

PubMed2006

Design and implementation of a point-of-care computerized system for drug therapy in Stockholm metropolitan health region--Bridging the gap between knowledge and practice.

INTRODUCTION: Stockholm County Council is the largest health care provider in Sweden with an annual budget of US$ 5 billion and catering the needs of a metropolitan population of 2 million people. About 10% of health care costs are used on drugs. In 1996 Stockholm County Council decided to address the main problems associated with the process and the quality of drug prescribing. METHODS: A multiyear strategy was designed, including the establishment of a strong evidence-based organisation, Drug and Therapeutics Committees and editorial resources to adapt information to the IT-media and the development of the IT-architecture. The development and implementation of computerized tools such as a physician drug order entry system including decision support, a drug information website and electronic transmission of prescriptions were started in 1996. RESULTS: The implementation was slow at the point-of-care units. It took about 6 years before the implementation process gained speed. In September 2005 almost 1000 doctors could use the decision support system for prescribing drugs and more than 70% of all prescriptions were transmitted electronically in our region. CONCLUSIONS: The work with the strategy has shown that improvements in drug use can be accomplished by providing access to simple, rapid and safe electronic tools, but the information provided has to be associated with well-recognized regional and national expert organisations.

Delivery of Health Care↗

PubMed2006

Nervous activity in a stem cell niche.

In this issue of Cell, report a new regulatory axis for the mobilization of hematopoietic stem cells that links these cells to the nervous system and bone in an unanticipated way. The new findings suggest that the nervous system, which has the inherent ability to integrate information from throughout the organism, may govern the local relationship between stem cells and their niches.

Animals↗

PubMed2005

Orientation-selective adaptation to first- and second-order patterns in human visual cortex.

Second-order textures-patterns that cannot be detected by mechanisms sensitive only to luminance changes-are ubiquitous in visual scenes, but the neuronal mechanisms mediating perception of such stimuli are not well understood. We used an adaptation protocol to measure neural activity in the human brain selective for the orientation of second-order textures. Functional MRI (fMRI) responses were measured in three subjects to presentations of first- and second-order probe gratings after adapting to a high-contrast first- or second-order grating that was either parallel or orthogonal to the probe gratings. First-order (LM) stimuli were generated by modulating the stimulus luminance. Second-order stimuli were generated by modulating the contrast (CM) or orientation (OM) of a first-order carrier. We used four combinations of adapter and probe stimuli: LM:LM, CM:CM, OM:OM, and LM:OM. The fourth condition tested for cross-modal adaptation with first-order adapter and second-order probe stimuli. Attention was diverted from the stimulus by a demanding task at fixation. Both first- and second-order stimuli elicited orientation-selective adaptation in multiple cortical visual areas, including V1, V2, V3, V3A/B, a newly identified visual area anterior to dorsal V3 that we have termed LO1, hV4, and VO1. For first-order stimuli (condition LM:LM), the adaptation was no larger in extrastriate areas than in V1, implying that the orientation-selective first-order (luminance) adaptation originated in V1. For second-order stimuli (conditions CM:CM and OM:OM), the magnitude of adaptation, relative to the absolute response magnitude, was significantly larger in VO1 (and for condition CM:CM, also in V3A/B and LO1) than in V1, suggesting that second-order stimulus orientation was extracted by additional processing after V1. There was little difference in the amplitude of adaptation between the second-order conditions. No consistent effect of adaptation was found in the cross-modal condition LM:OM, in agreement with psychophysical evidence for weak interactions between first- and second-order stimuli and computational models of separate mechanisms for first- and second-order visual processing.

Adaptation, Physiological↗

PubMed2005

TGF-beta type II receptor-deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo.

We have taken advantage of the Cre/lox system to generate a mouse model with inducible deficiency of transforming growth factor beta receptor II (TbetaRII). Using this approach, transforming growth factor beta (TGF-beta) signaling deficiency can be restricted to the hematopoietic system by bone marrow transplantation. Mice that received transplants with TbetaRII-/- bone marrow develop a lethal inflammatory disorder closely resembling that of TGF-beta1-null mice. Previous in vitro studies have suggested multiple roles for TGF-beta in T-cell development, including proliferation, apoptosis, and differentiation. We used our transplantation model to ask whether T-cell development is normal in the absence of TGF-beta signaling. The findings show for the first time in vivo and in fetal thymus organ culture (FTOC) that TGF-beta is not required for thymocytes to differentiate along the entire pathway of thymic T-cell development, as defined by the expression patterns of CD4, CD8, CD25, and CD44. In contrast to previous investigations, no increase of thymocyte apoptosis was observed. However, TbetaRII-deficient CD8+ thymocytes displayed a 2-fold increase in proliferation rate, as determined by bromodeoxyuridine (BrdU) incorporation in vivo. These results reinforce the importance of TGF-beta as an immune regulator critical for T-cell function.

Animals↗

PubMed2005

The role of Smad signaling in hematopoiesis.

The TGF-beta family of ligands, including TGF-beta, bone morphogenetic protein (BMP) and activin, signal through Smad pathways to regulate the fate of hematopoietic progenitor and stem cells during development and postnatally. BMP regulates hematopoietic stem cell (HSC) specification during development, while TGF-beta1, 2 and 3 are not essential for the generation of HSCs. BMP4 can increase proliferation of human hematopoietic progenitors, while TGF-beta acts as a negative regulator of hematopoietic progenitor and stem cells in vitro. In contrast, TGF-beta signaling deficiency in vivo does not affect proliferation of HSCs and does not affect lineage choice either. Therefore, the outcome of Smad signaling is very context dependent in hematopoiesis and regulation of hematopoietic stem and progenitor cells is more complicated in the bone marrow microenvironment in vivo than is seen in liquid cultures ex vivo. Smad signaling regulates hematopoiesis by crosstalk with other regulatory signals and future research will define in more detail how the various pathways interact and how the knowledge obtained can be used to develop advanced cell therapies.

Animals↗

PubMed2005

Altered primordial germ cell migration in the absence of transforming growth factor beta signaling via ALK5.

Transforming growth factor beta (TGFbeta) inhibits proliferation and promotes the migration of primordial germ cells (PGCs) towards explants of gonadal ridges in vitro. However, its effects in vivo are still unclear. Here, we analyzed the behavior of PGCs in embryos lacking TGFbeta signaling via the type I receptor ALK5. TGFbeta in vivo was neither a chemoattractant for PGCs, nor did it affect their proliferation during migration towards the gonadal ridges up to embryonic day (E)10. Unexpectedly, the absence of TGFbeta signaling in fact resulted in significant facilitation of PGC migration out of the hindgut, due to the reduced deposition of collagen type I surrounding the gut of Alk5-deficient mutant embryos. Migratory PGCs adhere strongly to collagen; therefore, reduced collagen type I along the gut may result in reduced adhesion, facilitating migration into the dorsal mesenterium and gonadal ridges. Our results provide new evidence for the role of TGFbeta signaling in migration of PGCs in vivo distinct from that described previously.

Activin Receptors, Type I↗

PubMed2005

Gene expression profiling demonstrates that TGF-beta1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-beta signaling.

Transforming growth factor-beta1 (TGF-beta) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-beta binds to receptor complexes consisting of TGF-beta receptor type II (TbetaRII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of TbetaRII/Alk5 can be relevant for TGF-beta signaling. We have screened for alternative receptors for TGF-beta and also for gene targets of TGF-beta signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-beta-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-beta. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-beta-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-beta signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.

Activin Receptors, Type I↗

PubMed2005

Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo.

OBJECTIVE: Maintained quiescence of hematopoietic stem cells (HSCs) is of critical importance to prevent premature exhaustion of the stem cell pool under conditions of hematopoietic stress. The growth inhibitory cytokine transforming growth factor beta (TGF-beta) has been shown to play a critical role in maintaining quiescence of HSCs in vitro. Here, we have used conditional knockout mice for the TGF-beta type I receptor (TbetaRI) to ask whether the naturally quiescent state of HSCs in vivo is dependent on TGF-beta signaling and thus whether TGF-beta serves as a protective factor for the stem cell pool during conditions of stress. METHODS: TbetaRI null and control bone marrow chimeras were subjected to repeated treatments with the cell cycle-specific cytotoxic drug 5-fluorouracil (5-FU) and surviving HSCs were assayed by competitive transplantation experiments. Exhaustion of stem cells was provoked by serially transplanting TGF-beta signaling-deficient as well as normal BM cells into lethally irradiated recipients, which were monitored for survival. RESULTS: Surprisingly, we found that TGF-beta receptor-deficient HSCs have similar susceptibility, compared to controls, to repeated 5-FU treatments, indicative of normally maintained quiescence in these cells. Likewise, hematopoietic failure occurred at similar stages in serially transplanted recipients of TbetaRI null and control BM, respectively, demonstrating normal consumption of the stem cell pool during hematopoietic stress. CONCLUSIONS: These findings clearly demonstrate that, despite a key role in vitro, TGF-beta does not provide the necessary signal that induces the quiescent state of HSCs and maintains the stem cell pool in vivo.

Animals↗

PubMed2004

Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes, endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) beta receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFbeta signalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFbeta type II receptor (TbetaRII) or ALK5. We show that TGFbeta/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFbeta1. Our data show that disruption of TGFbeta signalling in vascular endothelial cells results in reduced availability of TGFbeta1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

Activin Receptors, Type I↗

PubMed2004

Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.

Connective tissue growth factor (CTGF) is reported to be a target gene of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) in vitro. Its physiological role in angiogenesis and skeletogenesis during mouse development has been described recently. Here, we have mapped expression of CTGF mRNA during mouse heart development, postnatal adult life, and after experimental myocardial infarction. Furthermore, we investigated the relationship between CTGF and the BMP/TGFbeta signaling pathway in particular during heart development in mutant mice. Postnatally, CTGF expression in the heart became restricted to the atrium. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFbeta expression as well as activated forms of TGFbeta but not BMP, Smad effector proteins are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFbeta during the pathological fibrotic response.

Aging↗

PubMed2004

Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice.

Transforming growth factor beta (TGF-beta) is a potent inhibitor of hepatocyte proliferation in vitro and is suggested to be a key negative regulator of liver growth. To directly address the role of TGF-beta signaling in liver regeneration in vivo, the TGF-beta type II receptor gene (Tgfbr2) was selectively deleted in hepatocytes by crossing "floxed" Tgfbr2 conditional knockout mice with transgenic mice expressing Cre under control of the albumin promoter. Hepatocytes isolated from liver-specific Tgfbr2 knockout (R2LivKO) mice were refractory to the growth inhibitory effects of TGF-beta1. The peak of DNA synthesis after 70% partial hepatectomy occurred earlier (36 vs. 48 hours) and was 1.7-fold higher in R2LivKO mice compared with controls. Accelerated S-phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver. Regenerating R2LivKO liver showed evidence of increased signaling by activin A and persistent activity of the Smad pathway. Blockage of activin A signaling by the specific inhibitor follistatin resulted in increased hepatocyte proliferation at 120 hours, particularly in R2LivKO livers. In conclusion, TGF-beta regulates G(1) to S phase transition of hepatocytes, but intact signaling by TGF-beta is not required for termination of liver regeneration. Increased signaling by activin A may compensate to regulate liver regeneration when signaling through the TGF-beta pathway is abolished, and may be a principal factor in the termination of liver regeneration.

Activins↗

PubMed2004

Problem severity profiles of substance abusing women in European Therapeutic Communities: influence of psychiatric problems.

This article aims to search for a specific female, psychiatric profile based on a large European sample of substance dependent clients (828) entering therapeutic communities. First, all six areas of functioning of the EuropASI were included, using the composite scores to search for gender differences. Next, the 'psychiatric' status section was selected for further study. A binary logistic regression was performed with gender as the dependent variable, and nine individual psychiatric items, country, and age as predictors. According to this model a number of problem variables could be identified as being reported more often by women than by men in therapeutic community treatment. Women are more likely to report serious depression, problems in understanding, concentrating or remembering, being prescribed medication, and serious thoughts about suicide; they have also attempted suicide more often than men. Women find treatment for these psychological problems more important than their male counterparts. They also have a more severe history of abuse. Women in therapeutic communities may need specific treatment interventions for their more severe psychiatric needs.

Adult↗

PubMed2003

TGF-beta signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro.

Studies in vitro implicate transforming growth factor beta (TGF-beta) as a key regulator of hematopoiesis with potent inhibitory effects on progenitor and stem cell proliferation. In vivo studies have been hampered by early lethality of knock-out mice for TGF-beta isoforms and the receptors. To directly assess the role of TGF-beta signaling for hematopoiesis and hematopoietic stem cell (HSC) function in vivo, we generated a conditional knock-out model in which a disruption of the TGF-beta type I receptor (T beta RI) gene was induced in adult mice. HSCs from induced mice showed increased proliferation recruitment when cultured as single cells under low stimulatory conditions in vitro, consistent with an inhibitory role of TGF-beta in HSC proliferation. However, induced T beta RI null mice show normal in vivo hematopoiesis with normal numbers and differentiation ability of hematopoietic progenitor cells. Furthermore HSCs from T beta RI null mice exhibit a normal cell cycle distribution and do not differ in their ability long term to repopulate primary and secondary recipient mice following bone marrow transplantation. These findings challenge the classical view that TGF-beta is an essential negative regulator of hematopoietic stem cells under physiologic conditions in vivo.

Activin Receptors, Type I↗