Biology subjects

Govaerts, J.

Publications and source records attributed to Govaerts, J..

4 recordsLinked to original sources

bioRxiv2025

The CPEB ortholog Orb2 regulates brain size through the TRIM-NHL RNA-binding protein, Brain tumor

Neurodevelopment requires precise translational control, the disruption of which is implicated in various neurological disorders, including developmental delays, intellectual disability, and microcephaly. We report a novel role for the Drosophila CPEB-family protein Orb2, a translational regulator, in controlling brain size in a dose dependent manner. Loss of orb2 results in larval brain hypotrophy, whereas orb2 overexpression causes brain overgrowth. We demonstrate that orb2 is required for neural stem cell development from embryonic stages through larval neurogenesis. Structure-function analysis reveals that Orb2 RNA-binding activity promotes brain growth, while its poly-Q and ZZ domains act to restrain overgrowth. Further genetic and biochemical evidence indicates that orb2 functions upstream of the translational repressor Brain tumor (Brat), modulating Brat protein levels and, consequently, influencing brain size. These findings support a model wherein the antagonistic activities of Orb2 and Brat are critical for balanced brain growth during Drosophila neurodevelopment.

developmental biology↗

bioRxiv2025

The microcephaly protein Abnormal Spindle has an essential role in symmetrically dividing neural precursors to promote brain growth and development

Neurogenesis must be coordinated in time and space to ensure proper neural development. Defects in this process can lead to a variety of brain malformations that affect tissue size and architecture. Here we examine the spatiotemporal requirements of the Abnormal Spindle (Asp) protein and its human ortholog Abnormal Spindle-Like, Microcephaly Associated (ASPM) in a fly model of human microcephaly (MCPH). By utilizing the fly optic lobe, whose neurogenic program parallels that of mammals, and the genetic tools available in this organism, we uncover the progenitor cell types and critical neurogenesis window necessary for proper brain size and architecture. Asp has an essential function in symmetrically dividing neuroepithelial precursors, yet its expression in asymmetrically dividing neuroblasts alone is not sufficient for optic lobe development. Asp is highly expressed during both embryonic and larval neurogenesis stages, but embryonic expression is dispensable for making a properly sized adult brain. We also show that Asp/ASPMs interphase nuclear localization is not required for its ability to promote brain development. Expression of the human ASPM N-terminus can also significantly rescue fly brain defects, suggesting conserved mechanisms of function in brain growth control. These results support a model where Asp expression in symmetrically dividing precursors is required to generate a sufficient pool of progenitors prior to the cell fate switch to asymmetrically dividing neuroblasts in order to generate enough neuronal cells to make a properly sized brain.

developmental biology↗

bioRxiv2024

Chimeric aggregative multicellularity in absence of kin discrimination

Aggregative multicellularity is a cooperative strategy employed by some microorganisms. Unlike clonal expansion within protected environments during multicellular eukaryotic development, an aggregation strategy introduces the potential for genetic conflicts and exploitation by cheaters, threatening the stability of the social system. Myxococcus xanthus, a soil-dwelling bacterium, employs aggregative multicellularity to form multicellular fruiting bodies that produce spores in response to starvation. Studies of natural fruiting bodies show that this process is restricted to close kin or clonemates. Here, we investigate the mechanisms underlying kin recognition during development in M. xanthus. By co-culturing two distantly related M. xanthus strains under vegetative and starvation conditions, we observed that the strains segregate in both contexts. During vegetative growth, one strain antagonized the other using the type VI secretion system (T6SS). T6SS-mediated antagonism was also observed during development, resulting in monoclonal fruiting bodies when WT strains were mixed. In contrast, mixtures of T6SS knockout strains formed chimeric fruiting bodies, that produced viable spores from both strains. These findings suggest that T6SS is the primary mechanism of kin discrimination in distantly related M. xanthus strains, and its use ensures the development of monoclonal fruiting bodies and social integrity.

microbiology↗

bioRxiv2023

A lymph node-to-tumour PD-L1+macrophage circuit antagonizes dendritic cell immunotherapy

Immune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4+ and CD8+T cells, DCs stimulated immunosuppressive PD-L1+LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1+tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1+macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to deplete PD-L1+macrophages, suppress myeloid inflammation affecting the tumor bed and draining lymph nodes, and de-inhibit effector/stem-like memory T cells, eventually causing tumour regression. The synergistic interaction between the DC vaccine and PD-L1 blockade was lost when DCs were manipulated to lose Ifnar1or Ccr7 or when macrophages were depleted. Interestingly, clinical DC vaccines also potentiated lymphocyte-suppressive PD-L1+TAMs in patients bearing T cell-depleted tumours. Altogether, our results reveal the existence of a novel PD-L1+LAM/TAM-driven immunosuppressive pathway that can be elicited by DC vaccines, yet can be subverted for improving the outcome of immunotherapy.

immunology↗