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Self-organization of human dorsal-ventral forebrain structures by light induced SHH.

ABSTRACT: Organizing centers secrete morphogens that specify the emergence of germ layers and the establishment of the body's axes during embryogenesis. While traditional experimental embryology tools have been instrumental in dissecting the molecular aspects of organizers in model systems, they are impractical in human in-vitro model systems to dissect the relationships between signaling and fate along embryonic coordinates. To systematically study human embryonic organizer centers, we devised a collection of optogenetic ePiggyBac vectors to express a photoactivatable Cre-loxP recombinase, that allows the systematic induction of organizer structures by shining blue-light on human embryonic stem cells (hESCs). We used a light stimulus to geometrically confine SHH expression in neuralizing hESCs. This led to the self-organization of mediolateral neural patterns. scRNA-seq analysis established that these structures represent the dorsal-ventral forebrain, at the end of the first month of development. Here, we show that morphogen light-stimulation is a scalable tool that induces self-organizing centers.

SUBMITTER: De Santis R

PROVIDER: S-EPMC8604999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Self-organization of human dorsal-ventral forebrain structures by light induced SHH

Project description:We report the use of a light stimulus to geometrically confine SHH expression in neuralizing hESCs. This led to the self-organization of mediolateral neural patterns. scRNA-seq analysis established that these structures represent the dorsal-ventral forebrain, at the end of the first month of development. Here, we show that morphogen light-stimulation is a scalable tool that induces self-organizing centers.

2021-10-11 | GSE163505 | GEO

Self-organization of human dorsal-ventral forebrain structures by light induced SHH

Project description:Self-organization of human dorsal-ventral forebrain structures by light induced SHH

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SHH signaling mediated by a prechordal and brain enhancer controls forebrain organization.

Project description:Sonic hedgehog (SHH) signaling plays a pivotal role in 2 different phases during brain development. Early SHH signaling derived from the prechordal plate (PrCP) triggers secondary Shh induction in the forebrain, which overlies the PrCP, and the induced SHH signaling, in turn, directs late neuronal differentiation of the forebrain. Consequently, Shh regulation in the PrCP is crucial for initiation of forebrain development. However, no enhancer that regulates prechordal Shh expression has yet been found. Here, we identified a prechordal enhancer, named SBE7, in the vicinity of a cluster of known forebrain enhancers for Shh This enhancer also directs Shh expression in the ventral midline of the forebrain, which receives the prechordal SHH signal. Thus, the identified enhancer acts not only for the initiation of Shh regulation in the PrCP but also for subsequent Shh induction in the forebrain. Indeed, removal of the enhancer from the mouse genome markedly down-regulated the expression of Shh in the rostral domains of the axial mesoderm and in the ventral midline of the forebrain and hypothalamus in the mouse embryo, and caused a craniofacial abnormality similar to human holoprosencephaly (HPE). These findings demonstrate that SHH signaling mediated by the newly identified enhancer is essential for development and growth of the ventral midline of the forebrain and hypothalamus. Understanding of the Shh regulation governed by this prechordal and brain enhancer provides an insight into the mechanism underlying craniofacial morphogenesis and the etiology of HPE.

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GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium.

Project description:Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations.

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Evolution of Shh endoderm enhancers during morphological transition from ventral lungs to dorsal gas bladder.

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The subcortical and neurochemical organization of the ventral and dorsal attention networks.

Project description:Attention is a core cognitive function that filters and selects behaviourally relevant information in the environment. The cortical mapping of attentional systems identified two segregated networks that mediate stimulus-driven and goal-driven processes, the Ventral and the Dorsal Attention Networks (VAN, DAN). Deep brain electrophysiological recordings, behavioral data from phylogenetic distant species, and observations from human brain pathologies challenge purely corticocentric models. Here, we used advanced methods of functional alignment applied to resting-state functional connectivity analyses to map the subcortical architecture of the Ventral and Dorsal Attention Networks. Our investigations revealed the involvement of the pulvinar, the superior colliculi, the head of caudate nuclei, and a cluster of brainstem nuclei relevant to both networks. These nuclei are densely connected structural network hubs, as revealed by diffusion-weighted imaging tractography. Their projections establish interrelations with the acetylcholine nicotinic receptor as well as dopamine and serotonin transporters, as demonstrated in a spatial correlation analysis with a normative atlas of neurotransmitter systems. This convergence of functional, structural, and neurochemical evidence provides a comprehensive framework to understand the neural basis of attention across different species and brain diseases.

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The large-scale organization of shape processing in the ventral and dorsal pathways.

Project description:Although shape perception is considered a function of the ventral visual pathway, evidence suggests that the dorsal pathway also derives shape-based representations. In two psychophysics and neuroimaging experiments, we characterized the response properties, topographical organization and perceptual relevance of these representations. In both pathways, shape sensitivity increased from early visual cortex to extrastriate cortex but then decreased in anterior regions. Moreover, the lateral aspect of the ventral pathway and posterior regions of the dorsal pathway were sensitive to the availability of fundamental shape properties, even for unrecognizable images. This apparent representational similarity between the posterior-dorsal and lateral-ventral regions was corroborated by a multivariate analysis. Finally, as with ventral pathway, the activation profile of posterior dorsal regions was correlated with recognition performance, suggesting a possible contribution to perception. These findings challenge a strict functional dichotomy between the pathways and suggest a more distributed model of shape processing.

| S-EPMC5659821 | biostudies-literature

TGFβ-signalling and FOXG1 expression hallmark astrocyte lineage diversity in the murine ventral and dorsal forebrain

Project description:Heterogeneous astrocyte populations are defined by diversity in cellular environment, progenitor identity or function. Yet, little is known about the extent of the heterogeneity and how this diversity is acquired during development. We used SILAC and quantitative proteomics to characterise primary murine telencephalic progenitor cells from FOXG1 (forkhead box G1)-cre driven Tgfbr2 (transforming growth factor beta receptor 2) knockout mice and identified differential protein expression of the astrocyte proteins GFAP (glial fibrillary acidic protein) and MFGE8 (milk fat globule-EGF factor 8). Biochemical and histological investigations revealed distinct populations of astrocytes in the dorsal and ventral telencephalon marked by GFAP or MFGE8 protein expression. The two subtypes differed in their response to TGFβ-signalling. Impaired TGFβ-signalling affected numbers of GFAP-astrocytes in the ventral telencephalon. In contrast, TGFβ reduced MFGE8 expression in astrocytes deriving from both regions. Additionally, lineage tracing revealed that both GFAP and MFGE8 astrocyte subtypes derived partly from FOXG1-expressing neural precursor cells.

2022-03-02 | PXD005072 | Pride

Retinotopic organization of human ventral visual cortex.

Project description:Functional magnetic resonance imaging studies have shown that human ventral visual cortex anterior to human visual area V4 contains two visual field maps, VO-1 and VO-2, that together form the ventral occipital (VO) cluster (Brewer et al., 2005). This cluster is characterized by common functional response properties and responds preferentially to color and object stimuli. Here, we confirm the topographic and functional characteristics of the VO cluster and describe two new visual field maps that are located anterior to VO-2 extending across the collateral sulcus into the posterior parahippocampal cortex (PHC). We refer to these visual field maps as parahippocampal areas PHC-1 and PHC-2. Each PHC map contains a topographic representation of contralateral visual space. The polar angle representation in PHC-1 extends from regions near the lower vertical meridian (that is the shared border with VO-2) to those close to the upper vertical meridian (that is the shared border with PHC-2). The polar angle representation in PHC-2 is a mirror reversal of the PHC-1 representation. PHC-1 and PHC-2 share a foveal representation and show a strong bias toward representations of peripheral eccentricities. Both the foveal and peripheral representations of PHC-1 and PHC-2 respond more strongly to scenes than to objects or faces, with greater scene preference in PHC-2 than PHC-1. Importantly, both areas heavily overlap with the functionally defined parahippocampal place area. Our results suggest that ventral visual cortex can be subdivided on the basis of topographic criteria into a greater number of discrete maps than previously thought.

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Diurnal rhythms across the human dorsal and ventral striatum.

Project description:The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.

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