Biology subjects

Vogt, D.

Publications and source records attributed to Vogt, D..

18 recordsLinked to original sources

bioRxiv2026

Spatiotemporal differences in salmon nutrient inputs restructure functional and taxonomic fungal communities in riparian system

O_LISpawning salmon transport marine-derived nutrients (MDN) into riparian forests, influencing soil, plant, and animal communities, yet their effects on fungal communities remain poorly understood. C_LIO_LIWe used DNA metabarcoding to examine fungal responses to three spatial patterns of salmon-derived nitrogen (N) in southwest Alaska: (i) patchy inputs from wildlife-deposited carcasses, (ii) a 21-year carcass relocation experiment, and (iii) natural N gradients with distance from streams. C_LIO_LIDecomposing carcasses increased saprotrophic fungal diversity, identifying taxa responsible for salmon carcass decomposition. Long-term carcass relocation reduced diversity of medium-distance fringe ectomycorrhizal fungi (EMF), whereas recent, patchy carcass inputs increased diversity of both medium-distance fringe and long-distance EMF--guilds often associated with low-nutrient environments. Along natural stream N gradients, EMF responses varied markedly within functional guilds and genera, revealing unexpected variation in N sensitivity among closely related taxa. C_LIO_LIPulsed, spatially heterogeneous nutrient inputs enhanced diversity of typically nitrophobic EMF, likely reflecting their capacity to maintain extensive mycelial networks, exploit nutrient hotspots, and mobilize organic N and phosphorus. The diversity of responses along natural N gradients suggests that mechanisms linking EMF traits to nutrient acquisition and tolerance remain unresolved. Our findings emphasize the importance of linking fungal community composition with functional attributes and nutrient dynamics. C_LI

ecology↗

bioRxiv2026

Neurobehavioral impacts of the autism risk gene, WAC: Studies involving C. elegans and Mice

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a broad spectrum of behavioral impairments. While multiple genetic and environmental factors are attributed to its cause, biological underpinnings are still poorly understood. We investigated an ASD-associated gene, WAC, for its neurobehavioral aspects using C. elegans and mice. Studies of C. elegans with wac gene deletions (wac-1.1 and wac-1.2) showed enhanced acetylcholine-associated behavior, as indicated by the aldicarb assay. No alteration in acetylcholine levels or acetylcholinesterase activity was observed. Upon further investigation, we found that the elevated cholinergic transmission resulted from increased activity of nicotinic acetylcholine receptors (nAChRs). Additionally, we observed reduced motility and dopamine-associated behaviors, along with a reduced ability to switch from crawling to swimming, a serotonin-dependent behavior. Upregulation in mRNA expression of the lev-1 gene was observed. Conversely, a feedback-counterbalancing response in the form of downregulated genes, acr-2, unc-17, unc-63, and unc-50, was also observed. Surprisingly, lev-1 RNAi did not reverse the enhanced cholinergic transmission in PHX2587 worms, indicating the involvement of other players. To validate our findings, we also assessed CHRNA7 levels in Wac+/- mice. While some genetic compensation was observed in heterozygous mice, we found a direct, inverse correlation between Wac mRNA expression and CHRNA7 levels in the mouse brain cortex, corroborating our findings from C. elegans. Overall, these studies indicate that wac gene deletion in C. elegans exhibits a neurotransmitter alteration that is relatable to ASD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/709202v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1771dc4org.highwire.dtl.DTLVardef@1434b4eorg.highwire.dtl.DTLVardef@10525ecorg.highwire.dtl.DTLVardef@fcd8a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans

Deposition of CENP-A, the histone H3 variant considered an epigenetic landmark of centromeres, reflects cell-cycle-regulated assembly of M18BP1, HJURP, and PLK1 on a divalent MIS18/{beta} scaffold. The localization determinants of this machinery remain poorly characterized. Here we report that artificial M18BP1 dimerization bypasses MIS18/{beta}, allowing the identification of at least four determinants of M18BP1 centromere localization. These include the SANTA domain, of which we report the first structure, as well as linear motifs in disordered neighboring regions, of which we characterize the interaction footprint on the CENP-A associated 16-subunit constitutive centromere-associated network (CCAN). Our observations imply that M18BP1, after dimerization, is necessary and sufficient for centromere localization. Its cell-cycle-dependent dimerization on MIS18/{beta} promotes initial recognition of a multivalent centromeric assembly of old CENP-A and associated proteins, followed by cooption of PLK1 and HJURP and new CENP-A deposition. Our results shed new light on the determinants of centromere epigenetic inheritance in humans.

cell biology↗

bioRxiv2025

Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model

In addition to dementia, Alzheimers patients suffer from sleep impairments and aberrations in sleep-dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimers progression. We tested the degree to which transplantation of healthy donor interneuron progenitors would restore slow oscillation rhythm in young APP mice. We harvested medial ganglionic eminence (MGE) progenitors from mouse embryos and transplanted them into host APP mutant cortices. 3D light-sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage-sensitive dye imaging showed functional integration and slow oscillation rescue in absence or presence of optogenetic stimulation. Our work provides proof-of-concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP mice and potentially those of Alzheimers patients.

neuroscience↗

bioRxiv2024

Interactions with multiple inner kinetochore proteins determine mitotic localization of FACT

The FAcilitates Chromatin Transcription (FACT) complex is a dimeric histone chaperone that operates on chromatin during transcription and replication. FACT also interacts with a specialized centromeric nucleosome containing the histone H3 variant CENP-A and with CENP-TW, two subunits of CCAN, a 16-protein complex associated with CENP-A. The significance of these interactions remains elusive. Here, we show that FACT has multiple additional binding sites on CCAN. The interaction with CCAN is strongly stimulated by casein kinase II (CK2) phosphorylation of FACT. Mitotic localization of FACT to kinetochores is strictly dependent on specific CCAN subcomplexes. Unexpectedly, we also find that DNA readily displaces FACT from CCAN, suggesting that FACT becomes recruited through a pool of CCAN that is not stably integrated into chromatin. Collectively, our results point to a potential role of FACT in chaperoning CCAN during transcription or in the stabilization of CCAN at the centromere during the cell cycle. TeaserDNA-sensitive, direct interactions with multiple inner kinetochore subunits deliver FACT to the kinetochore.

biochemistry↗

bioRxiv2024

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function in mice that will pave the way for future molecular studies into DESSH. These studies present two new animals that begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

neuroscience↗

bioRxiv2023

Kit Ligand and Kit receptor tyrosine kinase sustain synaptic inhibition of Purkinje Cells

The cell-type specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders. Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/542885v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1d53d9eorg.highwire.dtl.DTLVardef@c05c4borg.highwire.dtl.DTLVardef@eb58eeorg.highwire.dtl.DTLVardef@11b8431_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Distinct hyperactive RAS/MAPK alleles converge on common GABAergic interneuron core programs

RAS/MAPK gene dysfunction underlies various cancers and neurocognitive disorders. While the role of RAS/MAPK genes have been well studied in cancer, less is known about their function during neurodevelopment. There are many genes that work in concert to regulate RAS/MAPK signaling, suggesting that if common brain phenotypes could be discovered they could have a broad impact on the many other disorders caused by distinct RAS/MAPK genes. We assessed the cellular and molecular consequences of hyperactivating the RAS/MAPK pathway using two distinct genes in a cell type previously implicated in RAS/MAPK-mediated cognitive changes, cortical GABAergic interneurons. We uncovered some GABAergic core programs that are commonly altered in each of the mutants. Notably, hyperactive RAS/MAPK mutants bias developing cortical interneurons towards those that are somatostatin+. The increase in somatostatin+ interneurons could also be induced by elevated neural activity and we show the core RAS/MAPK signaling pathway is one mechanism by which this occurs. Overall, these findings present new insights into how different RAS/MAPK mutations can converge on GABAergic interneurons, which may be important for other RAS/MAPK genes/disorders.

neuroscience↗

bioRxiv2022

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.

neuroscience↗

bioRxiv2022

A murine Wac model exhibits phenotypes relevant to DeSanto-Shinawi Syndrome

Several monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments, including autism, attention deficit hyperactivity disorder (ADHD) and seizures. Limited studies and resources are available to make meaningful headway into the underlying mechanisms that result in these symptoms. One such example, DeSanto-Shinawi Syndrome (DESSH), is a rare disorder caused by mutations in the WAC gene. Those diagnosed with DESSH experience craniofacial alterations as well as cognitive symptoms that include autism, ADHD and seizures. However, no thorough studies from a mammalian model exist to understand how these changes occur. To overcome this, we generated constitutive murine Wac mutants and assessed phenotypes that are relevant to humans diagnosed with DESSH. Wac mutants have craniofacial, anatomical, behavioral and seizure susceptibility that are relevant to DESSH; this new model is suited to study some of the core symptoms of DESSH and the biology of Wac.

neuroscience↗

bioRxiv2022

Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization

Centromeres are specialized chromosome loci that seed the kinetochore, a large protein complex that effects chromosome segregation. The organization of the interface between the kinetochore and the specialized centromeric chromatin, marked by the histone H3 variant CENP-A, remains incompletely understood. A 16-subunit complex, the constitutive centromere associated network (CCAN), bridges CENP-A to the spindle-binding moiety of the kinetochore. Here, we report a cryo-electron microscopy structure of human CCAN. We highlight unique features such as the pseudo GTPase CENP-M and report how a crucial CENP-C motif binds the CENP-LN complex. The CCAN structure has also important implications for the mechanism of specific recognition of the CENP-A nucleosome. A supported model depicts the interaction as fuzzy and identifies the disordered CCAN subunit CENP-C as only determinant of specificity. A more speculative model identifies both CENP-C and CENP-N as specificity determinants, but implies CENP-A may be in a hemisome rather than in a classical octamer.

biochemistry↗

bioRxiv2021

Parallel functional testing identifies enhancers active in early postnatal mouse brain

Enhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in normal and pathogenic brain development.

neuroscience↗

bioRxiv2020

Assembly principles and stoichiometry of a complete human kinetochore module

Centromeres are epigenetically determined chromosomal loci that seed kinetochore assembly to promote chromosome segregation during cell division. CENP-A, a centromere-specific histone H3 variant, establishes the foundations for centromere epigenetic memory and kinetochore assembly. It recruits the constitutive centromere-associated network (CCAN), which in turn assembles the microtubule-binding interface. How the specific organization of centromeric chromatin relates to kinetochore assembly and to centromere identity through cell division remains conjectural. Here, we break new ground by reconstituting a functional full-length version of CENP-C, the largest human CCAN subunit and a blueprint of kinetochore assembly. We show that full-length CENP-C, a dimer, binds stably to two nucleosomes, and permits further assembly of all other kinetochore subunits in vitro with relative ratios that closely match those of endogenous human kinetochores. Our results imply that human kinetochores emerge from clustering multiple copies of a fundamental module, and may have important implications for trans-generational inheritance of centromeric chromatin.

biochemistry↗

bioRxiv2020

A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice.

BackgroundEnvironmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations. MethodsWe performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry. ResultsMIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex. ConclusionsMIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.

neuroscience↗

bioRxiv2020

A human TSC1 mutation screening platform in GABAergic cortical interneurons for Genotype to Phenotype assessments

Tuberous Sclerosis Complex is a complex syndrome that affects multiple organs and is caused by dysfunction of either the TSC1 or TSC2 genes. One of the least understood features of TSC is the impact of TSC1&2 variants on brain phenotypes, including elevated rates of autism spectrum disorder and seizures. Moreover, while a great deal of work has uncovered how loss of either gene can alter various neural cell types, the impact of many variants in TSC and on these cell types is poorly understood. In particular, missense variants that cause minor changes in the proteins are expected to cause functional changes that differ from a complete loss of the protein. Herein, we examined how some missense variants in TSC1 impacted the development of cortical inhibitory interneurons, a cell type whose molecular, cellular and physiological properties are known to be altered after loss of mouse Tsc1. Importantly, we found that most missense variants complemented phenotypes caused by loss of Tsc1 and resulting in elevated MTOR activity as well as several cell intrinsic physiological properties. However, distinct variants showed deficits in complementing an increase in parvalbumin levels, which is observed after loss of Tsc1 and demonstrated smaller amplitudes of after hyperpolarizations. These data suggest subtle but sensitive phenotypes can be detected by some TSC1 missense variants and provide an in vivo system in which to better assess TSC variants.

neuroscience↗

bioRxiv2019

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons

Neurofibromatosis-1 (NF-1) is a monogenic disorder caused by mutations in the NF1 gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by cafe-au-lait skin spots and benign tumors, the mechanisms underlying cognitive changes in NF-1 are poorly understood. Cortical GABAergic interneurons (CINs) are implicated in NF-1 pathology but cellular and molecular changes to CINs are poorly understood. We deleted Nf1 from the medial ganglionic eminence (MGE), which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Loss of Nf1 led to a persistence of immature oligodendrocytes that prevented later born oligodendrocytes from occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss of Nf1 results in a graded decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism whereby Nf1 regulates a critical CIN developmental milestone.

neuroscience↗

bioRxiv2019

The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis (TS) gene, Tsc1, which inhibits mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. These changes also occur when only one allele of Tsc1 is deleted, making these findings relevant to individuals with TS. Notably, treatment with rapamycin, which inhibits MTOR, reverses these changes in adult mice. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to some neuropsychiatric symptoms observed in TS. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

neuroscience↗

bioRxiv2018

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer.

Epidemiological and clinical evidence points to cancer as a comorbidity in people with autism spectrum disorders (ASD). A significant overlap of genes and biological processes between both diseases has also been reported. Here, for the first time, we compared the gene expression profiles of ASD frontal cortex tissues and 22 cancer types obtained by differential expression meta-analysis. Four cancer types (brain, thyroid, kidney, and pancreatic cancers) presented a significant overlap in gene expression deregulations in the same direction as ASD whereas two cancer types (lung and prostate cancers) showed differential expression profiles significantly deregulated in the opposite direction from ASD. Functional enrichment and LINCS L1000 based drug set enrichment analyses revealed the implication of several biological processes and pathways that were affected jointly in both diseases, including impairments of the immune system, and impairments in oxidative phosphorylation and ATP synthesis among others. Our data also suggest that brain and kidney cancer have patterns of transcriptomic dysregulation in the PI3K/AKT/MTOR axis that are similar to those found in ASD. These shared transcriptomic alterations could help explain epidemiological observations suggesting direct and inverse comorbid associations between ASD and particular cancer types.

systems biology↗