The Temporal Contribution of the Gbx2 Lineage to Cerebellar Neurons

The cerebellum (Cb) is an exquisite structure that controls elaborate motor behaviors and is essential for sensory-motor learning. During development, the Cb is derived from rhombomere 1 (r1). Within this embryonic compartment, precursors in r1 are patterned by signaling cues originating from the isthmus organizer (IsO) and subsequently undergo complex morphogenic movements to establish their final position in the mature Cb. The transcription factor Gbx2 is expressed in the developing Cb and is intimately involved in organizing and patterning the Cb. Nevertheless, how precursors expressing Gbx2 at specific embryonic time points contribute to distinct cell types in the adult Cb is unresolved. In this study, we used Genetic Inducible Fate Mapping (GIFM) to mark Gbx2-expressing precursors with fine temporal resolution and to subsequently track this lineage through embryogenesis. We then determined the terminal neuronal fate of the Gbx2 lineage in the adult Cb. Our analysis demonstrates that the Gbx2 lineage contributes to the Cb with marking over the course of five stages: Embryonic day 7.5 (E7.5) through E11.5. The Gbx2 lineage gives rise to Purkinje cells, granule neurons, and deep cerebellar neurons across these marking stages. Notably, the contribution of the Gbx2 lineage shifts as development proceeds with each marking stage producing a distinct profile of mature neurons in the adult Cb. These findings demonstrate the relationship between the temporal expression of Gbx2 and the terminal cell fate of neurons in the Cb. Based on these results, Gbx2 is critical to Cb development, not only for its well-defined role in positioning and maintaining the IsO, but also for guiding the development of Cb precursors and determining the identity of Cb neurons

The Lineage Contribution and Role of Gbx2 in Spinal Cord Development

BACKGROUND: Forging a relationship between progenitors with dynamically changing gene expression and their terminal fate is instructive for understanding the logic of how cell-type diversity is established. The mouse spinal cord is an ideal system to study these mechanisms in the context of developmental genetics and nervous system development. Here we focus on the Gastrulation homeobox 2 (Gbx2) transcription factor, which has not been explored in spinal cord development. METHODOLOGY/PRINCIPAL FINDINGS: We determined the molecular identity of Gbx2-expressing spinal cord progenitors. We also utilized genetic inducible fate mapping to mark the Gbx2 lineage at different embryonic stages in vivo in mouse. Collectively, we uncover cell behaviors, cytoarchitectonic organization, and the terminal cell fate of the Gbx2 lineage. Notably, both ventral motor neurons and interneurons are derived from the Gbx2 lineage, but only during a short developmental period. Short-term fate mapping during mouse spinal cord development shows that Gbx2 expression is transient and is extinguished ventrally in a rostral to caudal gradient. Concomitantly, a permanent lineage restriction boundary ensures that spinal cord neurons derived from the Gbx2 lineage are confined to a dorsal compartment that is maintained in the adult and that this lineage generates inhibitory interneurons of the spinal cord. Using lineage tracing and molecular markers to follow Gbx2-mutant cells, we show that the loss of Gbx2 globally affects spinal cord patterning including the organization of interneuron progenitors. Finally, long-term lineage analysis reveals that the presence and timing of Gbx2 expression in interneuron progenitors results in the differential contribution to subtypes of terminally differentiated interneurons in the adult spinal cord. CONCLUSIONS/SIGNIFICANCE: We illustrate the complex cellular nature of Gbx2 expression and lineage contribution to the mouse spinal cord. In a broader context, this study provides a direct link between spinal cord progenitors undergoing dynamic changes in molecular identity and terminal neuronal fate

Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP)

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group’s discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public

Three-dimensional reconstruction of autologous vein bypass graft distal anastomoses imaged with magnetic resonance: clinical and research applications

AbstractHigh-resolution magnetic resonance imaging was combined with computational modeling to create focused three-dimensional reconstructions of the distal anastomotic region of autologous vein peripheral bypass grafts in a preliminary series of patients. Readily viewed on a personal computer or printed as hard copies, a detailed appreciation of in vivo postoperative features of the anastomosis is possible. These reconstructions are suitable for analysis of geometric features, including vessel caliber, tortuosity, anastomotic angles, and planarity. Some potential clinical and research applications of this technique are discussed

Three-dimensional reconstruction of autologous vein bypass graft distal anastomoses imaged with magnetic resonance: clinical and research applications

AbstractHigh-resolution magnetic resonance imaging was combined with computational modeling to create focused three-dimensional reconstructions of the distal anastomotic region of autologous vein peripheral bypass grafts in a preliminary series of patients. Readily viewed on a personal computer or printed as hard copies, a detailed appreciation of in vivo postoperative features of the anastomosis is possible. These reconstructions are suitable for analysis of geometric features, including vessel caliber, tortuosity, anastomotic angles, and planarity. Some potential clinical and research applications of this technique are discussed

Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP)

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group’s discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public

Ectopic Wnt/Beta–Catenin Signaling Induces Neurogenesis in the Spinal Cord and Hindbrain Floor Plate

The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis

Town of Ludlow Master Plan. Part I: Envisioning 2030

The Master Plan Committee for the town of Ludlow contracted with the Pioneer Valley Planning Commission (PVPC) to prepare a new Master Plan. PVPC engaged the Department of Landscape Architecture and Regional Planning (LARP) at the University of Massachusetts Amherst to assist with a portion of the Master Plan work. This work included: executing analysis and assessment of existing community conditions, conducting a weekend visioning workshop, and developing land use scenarios for the purpose of providing concrete visualization of possible futures for the Town of Ludlow in 2030

MAP1B mutations cause intellectual disability and extensive white matter deficit

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Wholegenome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = −2.1SD, P = 5.1 × 10−8), 47% less corpus callosum (CC) volume (β = −2.4SD, P = 5.5 × 10−10) and lower brain-wide fractional anisotropy (P = 6.7 × 10−4). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.We are grateful to the participants and we thank the psychologists, nurses and staff, in particular Berglind Eiriksdottir, at the Research Recruitment Center and technicians and staff at Röntgen Domus. We also thank the staff at deCODE genetics core facilities and all our colleagues for their important contribution to this work. L.J. received support from the Swedish Society of Medicine, the Swedish Brain Foundation and Swedish Society for Medical Research. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreements’ no. 115008 (NEWMEDS) and no. 115300 (EUAIMS) of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7 funded grant no. 602450 (IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213 (PsychDPC).Peer Reviewe