Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9–A10 Dopaminergic Cells In Vivo

Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a−/− mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a−/− mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors

Impact of age and sex on carotid and peripheral arterial wall thickness in humans

Item does not contain fulltextBACKGROUND: Although previous studies have reported age-related wall thickening in carotid arteries, it is not clear whether this is a systemic phenomenon which is also apparent in peripheral conduit arteries or whether conduit wall thickness (WT) changes occur to a similar degree in men and women. AIM: To determine whether sex modifies the impact of ageing on WT or wall-to-lumen ratio (W:L) in atherosclerosis-prone (i.e. carotid artery, femoral, superficial femoral, popliteal artery) and atherosclerosis-resistant (i.e. brachial artery) conduit arteries. METHODS: We included 30 young (23 +/- 2 year; 15M : 15F) and 31 older (70 +/- 5 year; 18M : 13F) healthy subjects. High-resolution ultrasound was used to measure diameter, WT and wall-to-lumen ratio (W/L) in all arteries. RESULTS: Older subjects had increased WT and W/L in the carotid, femoral, superficial femoral, popliteal and brachial arteries (all P < 0.05). Compared with women, men demonstrated larger diameter and WT (both P < 0.01) across all arteries. Sex did not impact upon age-related changes in WT or W/L (P = 0.39 and 0.43 respectively). CONCLUSION: Our data suggest that age-related wall thickening, evident in the carotid artery, is also apparent in the arteries of the upper and lower limbs. The impact of age on wall thickening did not differ between men and women. These data support the presence of systemic increases in WT and W/L with age in apparently healthy humans, independent of sex

Response to: 'Reshape of the arterial wall as a slow reacting vascular structure'.

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Are changes in conduit artery function associated with intima-medial thickness in young subjects?

BACKGROUND: Impaired brachial artery endothelial function, assessed by flow-mediated dilation (FMD), provides a strong prognostic index of cardiovascular events in asymptomatic adults and those with cardiovascular disease. However, the relationship between FMD and carotid intima-medial thickness (cIMT) in young people is unknown. We hypothesized that impaired FMD, and decreased FMD over time, would predict cIMT. DESIGN AND METHODS: FMD and cIMT were assessed using high-resolution Doppler ultrasound in 53 children (18 boys) aged 10.3 +/- 0.3 years. FMD was assessed at baseline and 4-month and 30-month follow up. cIMT was assessed at 30-months. RESULTS: There was no significant relationship between FMD measured at baseline (10.7 +/- 4.3) and cIMT at 30 months. FMD was depressed at 4 months (7.2 +/- 3.5, p < 0.05) and 30 months (8.2 +/- 3.3, p = 0.51). However, there was no correlation between changes in FMD and cIMT. CONCLUSION: Changes in arterial function occurred in young subjects across a 30-month time frame; however, these changes were unrelated to individual differences in cIMT in this cohort. These data contrast with findings in adults and indicate that longer periods of functional impairment may be necessary before atherosclerotic wall thickening becomes apparent in young people, suggesting there is a 'window of opportunity' for preventative intervention strategies

Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas

Background Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated. Results Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. Conclusion It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningioma

Impact of wall thickness on conduit artery function in humans: is there a "Folkow" effect?

Item does not contain fulltextRegional heterogeneity in wall architecture and thickness may be present between conduit arteries in the upper and lower limbs in humans. These differences in wall architecture may, in turn, influence vascular responsiveness. Folkow proposed in the 1950s that heterogeneity in wall-to-lumen ratio (W:L) could contribute to differences in vascular responsiveness, but this hypothesis has never been directly confirmed in vivo. Our first aim was to examine wall thickness and W:L across arteries in the lower (common and superficial femoral) and upper limbs (brachial and radial) of healthy men (n=35) using high resolution ultrasound. In a subgroup (n=20) we examined the relationship between W:L of these arteries, physiological (flow-mediated dilation, FMD) and pharmacological vasodilation (glyceryl trinitrate, GTN). Diameter and wall thickness differed significantly across all arteries (ANOVA P<0.001), with smaller arteries having a relatively larger wall thickness. Moreover, we found a significant correlation between W:L and the FMD-response (r=0.55, P<0.001), which remained significant after correcting for the eliciting shear stress (r=0.47, P<0.001), indicating that W:L/FMD relationship was not primarily related to the impact of diameter on the shear rate stimulus to FMD. W:L also correlated strongly with the GTN-response (r=0.56, P<0.001) across all arteries studied. These results indicate that regional heterogeneity exists in W:L within, but also between, limbs. More importantly, differences in W:L contribute to differences in vascular functional responses, reinforcing the conceptual proposal of Folkow, who suggested that arteries with larger W:L exhibit exaggerated responses to vasoactive stimuli