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Schmitt, J.

Publications and source records attributed to Schmitt, J..

4 recordsLinked to original sources

Germination responses to experimental rainfall timing identify potential vulnerability to climate change across a clade of California wildflowers

The timing of germination, driven by seasonal cues, is critical for the life cycle of plants. Variation among species in germination responses can reflect evolutionary processes and adaptation to local climate and can affect vulnerability to changing conditions. Indeed, climate change is altering the timing of precipitation and associated temperatures, which may interact with germination cueing to affect the timing, quantity, and speed of germination. Germination responses to change can then have consequences for individual fitness, population dynamics, and species distributions. Here, we assessed responses to the timing of germination-triggering rains and corresponding temperatures for 11 species spanning the Streptanthus (s.l.) clade (Brassicaceae). To do so, we experimentally manipulated the onset date of rainfall events, measured effects on germination fraction and rate, and evaluated whether responses were constrained by evolutionary relationships across the phylogeny. We then explored the possible consequences of these responses to contemporary shifts in precipitation timing. Later onset rains and cooler temperatures significantly reduced germination rates for all species. Germination fractions decreased with later rains and cooler temperatures for all but three Caulanthus species. Species germination responses to the timing of rainfall and seasonal temperatures were phylogenetically constrained, with Caulanthus species appearing less sensitive. Further, six species are likely already experiencing significant decreases in germination fractions or rates (or both) with observed climate change, which has shifted the timing of rainfall towards the cooler, winter months in California. Overall, our findings highlight the importance of the germination responses to seasonal timing, how they have evolved across the clade, and their implications under climate change.

plant biology↗

Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury

The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). In this context, the canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that define the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood. By implementing experimental data, partial differential equation (PDE) modeling, as well as automated image analysis, we demonstrate that nuclear phosphorylation contributes to differences between YAP and TAZ localization in the nucleus and cytoplasm. Treatment of hepatocyte-derived cells with hepatotoxic acetaminophen (APAP) overdose induces a biphasic protein phosphorylation eventually leading to nuclear protein enrichment of YAP but not TAZ. APAP-dependent regulation of nuclear/cytoplasmic YAP shuttling is not an unspecific cellular response but relies on the sequential induction of reactive oxygen species (ROS), RAC-alpha serine/threonine-protein kinase (AKT, synonym: protein kinase B), as well as elevated nuclear interaction between YAP and AKT. Mouse experiments confirm this consecutive sequence of events illustrated by the expression of ROS-, AKT-, and YAP-specific gene signatures upon APAP administration. In summary, our data illustrate the importance of nuclear processes in the regulation of Hippo pathway activity. YAP and TAZ exhibit different shuttling dynamics, which explains distinct cellular responses of both factors under physiological and tissue-damaging conditions. SignificanceWe show that canonical view on the Hippo pathway must be extended by additional regulatory processes in cell nuclei. These processes significantly contribute to the activity of YAP and TAZ under unchallenged conditions (e.g., with cell density as physiological regulator of the Hippo kinase cassette) or under cell damaging conditions (e.g., after administration of APAP overdose). APAP-induced cellular damage activates YAP via distinct molecular processes as part of a cell-protective response.

molecular biology↗

Alteration of myocardial structure and function in RAF1associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs

Noonan syndrome (NS), the most common among the RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c.770C>T missense change. We characterize the molecular, structural and functional consequences of aberrant RAF1 -associated signaling on the cardiac models. Ultrastructural assessment of the sarcomere revealed a shortening of the I-bands along the Z disc area in both iPSC-derived RAF1S257L cardiomyocytes, and myocardial tissue biopsies. The disease phenotype was partly reverted by using both MEK inhibition, and a gene-corrected isogenic RAF1L257S cell line. Collectively, our findings uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction that remarkably recapitulates the human disease. These insights represent a basis to develop future targeted therapeutic approaches.

cell biology↗

Excessive self-grooming of Shank3 mutant mice is associated with gene dysregulation and imbalance between the striosome and matrix compartments in the striatum

Autism is characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with autism and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterised the behaviour of Shank3{Delta}11/{Delta}11 mice from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and modification of socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2, Dlgap1), G-protein-signalling pathways (e.g. Gnal, Prkcg1, and Camk2g), as well as excitation/inhibition balance (e.g. Gad2). Downregulated and upregulated genes were enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN), respectively. Several DEGs (Cnr1, Gnal1, Gad2, and Drd4) were reported as striosome markers. By studying the distribution of the glutamate decarboxylase GAD65, encoded by Gad2, we showed that the striosome compartment of Shank3{Delta}11/{Delta}11 mice was enlarged and displayed much higher expression of GAD65 compared to wild-type mice. Altogether, these results indicate altered gene expression in the striatum of SHANK3-deficient mice and strongly suggest, for the first time, that the impairment in behaviour of these mice are related to an imbalance striosomes/matrix.

neuroscience↗