Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion is among the strongest known genetic risk factors for neuropsychiatric disorders, including autism and schizophrenia. Brain imaging studies have reported disrupted large-scale functional connectivity in people with 22q11 deletion syndrome (22q11DS). However, the significance and biological determinants of these functional alterations remain unclear. Here, we use a cross-species design to investigate the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. We find that LgDel mice, an established mouse model of 22q11DS, exhibit age-specific patterns of functional MRI (fMRI) dysconnectivity, with widespread fMRI hyper-connectivity in juvenile mice reverting to focal hippocampal hypoconnectivity over puberty. These fMRI connectivity alterations are mirrored by co-occurring developmental alterations in dendritic spine density, and are both transiently normalized by developmental GSK3ß inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous hyper- to hypoconnectivity reconfiguration occurs also in human 22q11DS, where it affects hippocampal and cortical regions spatially enriched for synaptic genes that interact with GSK3ß, and autism-relevant transcripts. Functional dysconnectivity in somatomotor components of this network is predictive of age-dependent social alterations in 22q11.2 deletion carriers. Taken together, these findings suggest that synaptic-related mechanisms underlie developmentally mediated functional dysconnectivity in 22q11DS.

A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension.

Genetic variants in the third intron of the PRDM6 gene have been associated with BP traits in multiple GWAS. By combining fine mapping, massively parallel reporter assays, and gene editing, we identified super enhancers that drive the expression of PRDM6 and are partly regulated by STAT1 as the causal variants for hypertension. The heterozygous disruption of Prdm6 in mice expressing Cre recombinase under the control of mouse smooth muscle cell protein 22-α promoter (Prdm6fl/+ SM22-Cre) exhibited a markedly higher number of renin-producing cells in the kidneys at E18.5 compared with WT littermates and developed salt-induced systemic hypertension that was completely responsive to the renin inhibitor aliskiren. Strikingly, RNA-Seq analysis of the mouse aortas identified a network of PRDM6-regulated genes that are located in GWAS-associated loci for blood pressure, most notably Sox6, which modulates renin expression in the kidney. Accordingly, the smooth muscle cell-specific disruption of Sox6 in Prdm6fl/+ SM22-Cre mice resulted in a dramatic reduction of renin. Fate mapping and histological studies also showed increased numbers of neural crest-derived cells accompanied by increased collagen deposition in the kidneys of Prdm6fl/+ Wnt1Cre-ZsGreen1Cre mice compared with WT mice. These findings establish the role of PRDM6 as a regulator of renin-producing cell differentiation into smooth muscle cells and as an attractive target for the development of antihypertensive drugs.

Heterotopia in Individuals with 22q11.2 Deletion Syndrome.

BACKGROUND AND PURPOSE: MR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects' neuropsychiatric impairments. MATERIALS AND METHODS: Three raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups' most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions. RESULTS: Heterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome (n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae (n = 20; controls, n = 0; P < .001), periventricular cysts (n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia (n = 10; controls, n = 0; P = .007), and polymicrogyria (n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities. CONCLUSIONS: Taken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome.

Wnt Signaling Cascades and Their Role in Coronary Artery Health and Disease.

The Wnt signaling is classified as two distinct pathways of canonical Wnt/ß-catenin signaling, and the non-canonical pathways of planar cell polarity and Wnt/Ca2+ pathways. However, the scientific discoveries in recent years have shown that canonical and non-canonical Wnts pathways are intertwined and have complex interaction with other major signaling pathways such as hedgehog, Hippo and TOR signaling. Wnt signaling plays important roles in cell proliferation, differentiation and migration during embryonic development. The impairment of these pathways during embryonic development often leads to major congenital defects. In adult organisms Wnt expression is more restricted to proliferating tissues, where it plays a key role in tissue regeneration. In addition, the disruption of homeostatic processes of multicellular organisms may give rise to reactivation and/or altered activation of Wnt signaling, leading to development of malignant tumors and chronic diseases such as type-2 diabetes and adult cardiovascular diseases. Coronary artery disease (CAD) is the leading cause of death in the world. The disease is the consequences of two distinct disease processes: Atherosclerosis, a primarily inflammatory disease and plaque erosion, a disease process associated with endothelial cell defect and smooth muscle proliferation with only modest contribution of inflammatory cells. The atherosclerosis is itself a multifactorial disease that is initiated by lipid deposition and endothelial dysfunction, triggering vascular inflammation via recruitment and aggregation of monocytes and their transformation to foam cell by the uptake of modified low-density lipoprotein (LDL), culminating in an atheromatous plaque core formation. Further accumulation of lipids, infiltration and proliferation of vascular smooth muscle cells (VSMCs) and extracellular matrix deposition result in intimal hyperplasia. Myocardial infarction is the ultimate consequence of these processes and is caused by plaque rupture and hypercoagulation. In vivo studies have established the role of the Wnt pathway in all phases of atherosclerosis development, though much remains unknown or controversial. Less is known about the mechanisms that induce plaque erosion. The limited evidence in mouse models of Wnt coreceptor LRP6 mutation and heterozygous TCF7L2 knock out mice implicate altered Wnt signaling also in the pathogenesis of plaque erosion. In this article we focus and review the role of the Wnt pathway in CAD pathophysiology from clinical and experimental standpoints.

Crosstalk between vrille transcripts, proteins, and regulatory elements controlling circadian rhythms and development in Drosophila.

The vrille (vri) gene encodes a transcriptional repressor required for Drosophila development as well as circadian behavior in adults. Alternate first exons produce vri transcripts predicted to produce a short VRI isoform during development and long VRI in adults. A vri mutant (vri Δ679) lacking long VRI transcripts is viable, confirming that short VRI is sufficient for developmental functions, yet behavioral rhythms in vri Δ679 flies persist, showing that short VRI is sufficient for clock output. E-box regulatory elements that drive rhythmic long VRI transcript expression are required for developmental expression of short VRI transcripts. Surprisingly, long VRI transcripts primarily produce short VRI in adults, apparently due to a poor Kozak sequence context, demonstrating that short VRI drives circadian behavior. Thus, E-box-driven long VRI transcripts primarily control circadian rhythms via short VRI, whereas the same E-boxes drive short VRI transcripts that control developmental functions using short VRI.

Brain morphometry in 22q11.2 deletion syndrome: an exploration of differences in cortical thickness, surface area, and their contribution to cortical volume.

22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6-31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.

The Neuroanatomy of Autism Spectrum Disorder Symptomatology in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition associated with a high prevalence of neuropsychiatric conditions that include autism spectrum disorder (ASD). While evidence suggests that clinical phenotypes represent distinct neurodevelopmental outcomes, it remains unknown whether this translates to the level of neurobiology. To fractionate the 22q11.2DS phenotype on the level of neuroanatomy, we examined differences in vertex-wise estimates of cortical volume, surface area, and cortical thickness between 1) individuals with 22q11.2DS (n = 62) and neurotypical controls (n = 57) and 2) 22q11.2DS individuals with ASD symptomatology (n = 30) and those without (n = 25). We firstly observed significant differences in surface anatomy between 22q11.2DS individuals and controls for all 3 neuroanatomical features, predominantly in parietotemporal regions, cingulate and dorsolateral prefrontal cortices. We also established that 22q11.2DS individuals with ASD symptomatology were neuroanatomically distinct from 22q11.2DS individuals without ASD symptoms, particularly in brain regions that have previously been linked to ASD (e.g., dorsolateral prefrontal cortices and the entorhinal cortex). Our findings indicate that different clinical 22q11.2DS phenotypes, including those with ASD symptomatology, may represent different neurobiological subgroups. The spatially distributed patterns of neuroanatomical differences associated with ASD symptomatology in 22q11.2DS may thus provide useful information for patient stratification and the prediction of clinical outcomes.

VRILLE Controls PDF Neuropeptide Accumulation and Arborization Rhythms in Small Ventrolateral Neurons to Drive Rhythmic Behavior in Drosophila.

In Drosophila, the circadian clock is comprised of transcriptional feedback loops that control rhythmic gene expression responsible for daily rhythms in physiology, metabolism, and behavior. The core feedback loop, which employs CLOCK-CYCLE (CLK-CYC) activators and PERIOD-TIMELESS (PER-TIM) repressors to drive rhythmic transcription peaking at dusk, is required for circadian timekeeping and overt behavioral rhythms. CLK-CYC also activates an interlocked feedback loop, which uses the PAR DOMAIN PROTEIN 1ε (PDP1ε) activator and the VRILLE (VRI) repressor to drive rhythmic transcription peaking at dawn. Although Pdp1ε mutants disrupt activity rhythms without eliminating clock function, whether vri is required for clock function and/or output is not known. Using a conditionally inactivatable transgene to rescue vri developmental lethality, we show that clock function persists after vri inactivation but that activity rhythms are abolished. The inactivation of vri disrupts multiple output pathways thought to be important for activity rhythms, including PDF accumulation and arborization rhythms in the small ventrolateral neuron (sLNv) dorsal projection. These results demonstrate that vri acts as a key regulator of clock output and suggest that the primary function of the interlocked feedback loop in Drosophila is to drive rhythmic transcription required for overt rhythms.

Drosophila CRY Entrains Clocks in Body Tissues to Light and Maintains Passive Membrane Properties in a Non-clock Body Tissue Independent of Light.

Circadian (∼24 hr) clocks regulate daily rhythms in physiology, metabolism, and behavior via cell-autonomous transcriptional feedback loops. In Drosophila, the blue-light photoreceptor CRYPTOCHROME (CRY) synchronizes these feedback loops to light:dark cycles by binding to and degrading TIMELESS (TIM) protein. CRY also acts independently of TIM in Drosophila to alter potassium channel conductance in arousal neurons after light exposure, and in many animals CRY acts independently of light to repress rhythmic transcription. CRY expression has been characterized in the Drosophila brain and eyes, but not in peripheral clock and non-clock tissues in the body. To investigate CRY expression and function in body tissues, we generated a GFP-tagged-cry transgene that rescues light-induced behavioral phase resetting in cry03 mutant flies and sensitively reports GFP-CRY expression. In bodies, CRY is detected in clock-containing tissues including Malpighian tubules, where it mediates both light-dependent TIM degradation and clock function. In larval salivary glands, which lack clock function but are amenable to electrophysiological recording, CRY prevents membrane input resistance from falling to low levels in a light-independent manner. The ability of CRY to maintain high input resistance in these non-excitable cells also requires the K+ channel subunits Hyperkinetic, Shaker, and ether-a-go-go. These findings for the first time define CRY expression in Drosophila peripheral tissues and reveal that CRY acts together with K+ channels to maintain passive membrane properties in a non-clock-containing peripheral tissue independent of light.

Neural mechanisms of response inhibition and impulsivity in 22q11.2 deletion carriers and idiopathic attention deficit hyperactivity disorder.

•22q11DS offers a compelling model to understand the neural substrates of attentional dysfunction.•First study directly comparing neural function in 22q11DS vs. ADHD patients•22q11DS and ADHD patients show a shared deficit in RI-related activation.•ADHD patients showed greater activity in the middle frontal gyrus than 22q11DS during RI.•Neural activity is inversely correlated with self-reported Cognitive Impulsivity in 22q11DS.