Biology subjects

Mandl, C.

Publications and source records attributed to Mandl, C..

4 recordsLinked to original sources

bioRxiv2023

Growth/differentiation factor 15 controls primary cilia morphology in the murine ventricular-subventricular zone thereby affecting progenitor proliferation.

Growth/differentiation factor 15 (GDF15) and its receptor GDNF Family Receptor Alpha-Like (GFRAL) are expressed from embryonic development onwards in the germinal epithelium of the ganglionic eminence (GE), regulating proliferation and number of apical progenitors. However, the mechanisms underlying this regulation are not yet clear. We here show that GDF15 exerts this regulation by affecting ciliary signalling. Not only was GFRAL localized to primary cilia but, constitutive GDF15 ablation also led to shorter and thicker primary cilia. Lack of GDF15 affected the expression of histone deacetylase 6 (HDAC6) and ciliary adenylate cyclase 3 (ADCY3), thereby modifying acetylation of microtubules and endogenous Sonic Hedgehog (SHH) activation in neural progenitors. Application of exogenous GDF15 or pharmacological antagonism of HDAC6 or ADCY3 all increased cilia length and rescued proliferation and SHH signalling in mutant but not WT progenitors. Notably, HDAC6 expression and cilia length were changed only in the GE, were ciliary GFRAL localization was observed. In contrast, GFRAL was absent from primary cilia of hippocampal progenitors where GDF15 affected ADCY3 and SHH signalling, but not HDAC6 expression or cilia morphology. We conclude that ciliary GDF15 signalling regulates HDAC6 thereby affecting primary cilia elongation and proliferation in apical progenitors.

neuroscience↗

bioRxiv2022

Growth/differentiation factor 15 controls number of ependymal and neural stem cells in the ventricular/subventricular zone

Late in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE), especially in progenitors with characteristics of neural stem cells (NSCs). However, the function of GDF15 in this region is still unknown. We here show that apical progenitors in the E18 GE also express the GDF15 receptor and that ablation of GDF15 promotes proliferation and cell cycle progression of apically and subapically dividing progenitors. A similar phenotype was also observed in the adult ventricular subventricular zone (V-SVZ). At both ages, increased proliferation leads to the transient generation of more neuronal progenitors, which is compensated by cell death, and to a permanent increase in the number of ependymal cells and apical NSCs. We also found that GDF15 receptor-expressing cells display immunoreactivity for the epidermal growth factor receptor (EGFR), which is also involved in progenitor proliferation, and that manipulation of GDF15 affects the expression of EGFR in mutant progenitors. Moreover, our data indicate that EGFR signalling in WT and mutant progenitors relies on distinct transduction modes. However, only exposure to exogenous GDF15, but not to EGF, normalized proliferation and the number of apical progenitors, indicating that alteration in EGFR signalling is not the main mechanism by which GDF15 affects proliferation in the embryonic GE. Taken together, GDF15 directly regulates proliferation of apical progenitors in the developing GE, thereby affecting the number of total ependymal cells and NSCs in this region.

neuroscience↗

bioRxiv2022

Route of mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells

Respiratory tract resident memory T cells (Trm), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory Trm. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influence influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 Trm in lung and draining lymph node. Contralateral, compared to ipsilateral, intramuscular boosting broadened the distribution of LN Trm and T follicular helper cells, but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory, but augmented distribution to the respiratory mucosa. Of note, combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung Trm. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung Trm that can be further enhanced by an additional intranasal immunization.

immunology↗

bioRxiv2020

Basal Neural Stem Cells in the Subventricular Zone Drive Postnatal Neurogenesis with Apical Stem Cells Acting as Proliferation Gatekeepers

According to the current consensus, neural stem cells (NSCs) apically contacting the lateral ventricle generate differentiated progenitors by rare asymmetric divisions or by relocating to the basal side of the ventricular-subventricular zone V-SVZ. Both processes will then ultimately lead to the generation of adult-born olfactory bulb (OB) interneurons. In contrast to this view, we here found that adult-born OB interneurons largely derive from an additional NSC type resident in the basal V-SVZ. Despite being both capable of self-renewal and long-term quiescence, apical and basal NSCs differ in Nestin expression, primary cilia extension and frequency of cell division. The expression of Notch-related genes also differed between the two NSC groups and Notch-activation was greatest in apical NSCs. Apical downregulation of Notch-effector Hes1 decreased Notch activation while increasing proliferation across the niche and neurogenesis from apical NSCs. Underscoring their different roles in neurogenesis, lactation-dependent increase in neurogenesis was paralleled by extra activation of basal but not apical NSCs. Thus, basal NSCs support OB neurogenesis whereas apical NSCs impart Notch-mediated lateral inhibition across the V-SVZ.

cell biology↗