Biology subjects

Hartmann, J.

Publications and source records attributed to Hartmann, J..

24 records · Page 2Linked to original sources

bioRxiv2019

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), a main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. Using deletion, overexpression, and rescue of Fkbp5 exclusively in the PVN, we establish the fundamental importance of Fkbp5 in the HPA axis stress response. Furthermore, we show that Fkbp5 manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which Fkbp5 operates.

neuroscience↗

bioRxiv2019

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity between civilian and military PTSD cohorts. The top study-wide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these individuals, and deployment stress downregulated SNRNP35 expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex and SNRNP35 knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFC Snrnp35 expression.

genetics↗

bioRxiv2019

Structural basis for functional interactions in dimers of SLC26 transporters

The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain exerts a stabilizing effect on regions central in this dimer. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.

biochemistry↗

bioRxiv2018

TRPC3 is essential for functional heterogeneity of cerebellar Purkinje cells

Despite the canonical homogenous character of its organization, the cerebellum plays differential computational roles in distinct types of sensorimotor behaviors. However, the molecular and cell physiological underpinnings are unclear. Here we determined the contribution of transient receptor potential cation channel type C3 (TRPC3) to signal processing in different cerebellar modules. Using gain-of-function and loss-of-function mouse models, we found that TRPC3 controls the simple spike activity of zebrin-negative (Z-), but not of zebrin-positive (Z+), Purkinje cells. Moreover, in vivo TRPC3 also regulated complex spike firing and its interaction with simple spikes exclusively in Z- Purkinje cells. Finally, we found that eyeblink conditioning, related to Z- modules, but not compensatory eye movement adaptation, linked to Z+ modules, was affected in TRPC3 loss-of-function mice. Together, our results indicate that TRPC3 is essential for the cellular heterogeneity that introduces distinct physiological properties in an otherwise homogeneous population of Purkinje cells, conjuring functional heterogeneity in cerebellar sensorimotor integration.

neuroscience↗

bioRxiv2018

Profound functional and molecular diversity of mitochondria revealed by cell type-specific profiling in vivo

Mitochondria vary in morphology and function in different tissues, however little is known about their molecular diversity among cell types. To investigate mitochondrial diversity in vivo, we developed an efficient protocol to isolate cell type-specific mitochondria based on a new MitoTag mouse. We profiled the mitochondrial proteome of three major neural cell types in cerebellum and identified a substantial number of differential mitochondrial markers for these cell types in mice and humans. Based on predictions from these proteomes, we demonstrate that astrocytic mitochondria metabolize long-chain fatty acids more efficiently than neurons. Moreover, we identified Rmdn3 as a major determinant of ER-mitochondria proximity in Purkinje cells. Our novel approach enables exploring mitochondrial diversity on the functional and molecular level in many in vivo contexts.

cell biology↗

bioRxiv2017

Red wood-ant nests are traps for fault-related CH4 micro-seepage

Methane (CH4) is common on Earth, forms the major commercial natural gas reservoirs, and is a key component of the global carbon cycle, but its natural sources are not well-characterized. We present a geochemical dataset acquired from a red wood-ant (RWA; Formica polyctena) nest in the Neuwied Basin, a part of the East Eifel Volcanic Field (EEVF), focusing on methane (CH4), stable carbon isotope of methane ({delta}13C-CH4), RWA activity patterns, earthquakes, and earth tides. Nest gas and ambient air were continuously sampled in-situ and analyzed to detect microbial, thermogenic, and abiotic fault-related micro-seepage. Methane degassing was not synchronized with earth tides. Elevated CH4 concentrations in nest gas appear to result from a combination of microbial activity and fault-related emissions moving via through fault networks through the RWA nest. Two {delta}13C-CH4 signatures were identified in nest gas: -69{per thousand} and -37{per thousand}. The -69{per thousand} signature of {delta}13C-CH4 within the RWA nest is attributed to microbial decomposition of organic matter. This finding supports previous findings that RWA nests are hot-spots of microbial CH4. Additionally, the -37% {delta}13C-CH4 signature is the first evidence that RWA nests also serve as traps for fault-related emissions of CH4. The -37{per thousand} {delta}13C-CH4 signature can be attributed either to thermogenic/fault-related or to abiotic/fault-related CH4 formation originating from e.g. low-temperature gas-water-rock reactions in a continental setting at shallow depths (microseepage). Sources of these micro-seeps could be Devonian schists (\"Sphaerosiderith Schiefer\") with iron concretions (\"Eisengallen\"), sandstones, or the iron-bearing \"Klerf Schichten\". We cannot exclude overlapping micro-seepage of magmatic CH4 from the Eifel plume. Given the abundance of RWA nests on the landscape, their role as sources of microbial CH4 and traps for abiotically-derived CH4 should be included in estimation of methane emissions that are contributing to climatic change.

ecology↗