Biology subjects

Franke, J.

Publications and source records attributed to Franke, J..

4 recordsLinked to original sources

bioRxiv2021

Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of juvenile myogenic progenitors

Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that Neurofibromin-1 (Nf1) is not required in muscle fibers, but specifically in early postnatal myogenic progenitors (MPs), where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the MP pool resulting in reduced myonuclear accrual as well as reduced muscle stem cell numbers. This was caused by precocious induction of stem cell quiescence coupled to metabolic reprogramming of MPs impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/NOS pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Mek/Erk signaling supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safeguarding coordinated muscle growth and muscle stem cell pool establishment. Furthermore, our data suggest transmission of metabolic reprogramming across cellular differentiation, affecting fiber metabolism and function in NF1.

cell biology↗

bioRxiv2021

Mimicking extracellular matrix-mediated mechano-activation by antibodies to control signaling of the adhesion G protein-coupled receptor GPR126/ADGRG6

The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study we provide this information by combining classic second messenger detection with single cell atomic force microscopy. We establish a monoclonal antibody targeting the N terminus to stimulate GPR126 and compare it to the activation through its known ECM ligands collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be viewed as an allosteric module that can fine-tune receptor activation in a context-specific manner.

molecular biology↗

bioRxiv2021

Statistical determinants of visuomotor adaptation in a virtual reality three-dimensional environment

Neurorehabilitation in patients suffering from motor deficits relies on relearning or re-adapting motor skills. Yet our understanding of motor learning is based mostly on results from one or two-dimensional experimental paradigms with highly confined movements. Since everyday movements are conducted in three-dimensional space, it is important to further our understanding about the effect that gravitational forces or perceptual anisotropy might or might not have on motor learning along all different dimensions relative to the body. Here we test how well existing concepts of motor learning generalize to movements in 3D. We ask how a subjects variability in movement planning and sensory perception influences motor adaptation along three different body axes. To extract variability and relate it to adaptation rate, we employed a novel hierarchical two-state space model using Bayesian modeling via Hamiltonian Monte Carlo procedures. Our results show that differences in adaptation rate occur between the coronal, sagittal and horizontal planes and can be explained by the Kalman gain, i.e., a statistically optimal solution integrating planning and sensory information weighted by the inverse of their variability. This indicates that optimal integration theory for error correction holds for 3D movements and explains adaptation rate variation between movements in different planes.

neuroscience↗

bioRxiv2020

Cell autonomous requirement of Neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis

BackgroundNeurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy is mostly unknown. MethodsTo dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. ResultsNf1Lbx1 and Nf1Myf5 animals showed only mild defects in prenatal myogenesis. Nf1Lbx1 animals were perinatally lethal, while Nf1Myf5 animals survived only up to approx. 25 weeks. A comprehensive phenotypic characterization of Nf1Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. High-resolution respirometry confirmed enhanced oxidative metabolism in Nf1Myf5 muscles, which was concomitant to a fiber type shift from type 2B to type 2A and type 1. Moreover, Nf1Myf5 muscles showed hallmarks of decreased activation of mTORC1 and increased expression of atrogenes. Remarkably, loss of Nf1 promoted a robust activation of AMPK with a gene expression profile indicative of increased fatty acid catabolism. Additionally, we observed a strong induction of genes encoding catabolic cytokines in muscle Nf1Myf5 animals, in line with a drastic reduction of white, but not brown adipose tissue. ConclusionsOur results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle drives cross-tissue communication and mobilization of lipid reserves.

developmental biology↗