Biology subjects

Matsuzaki, F.

Publications and source records attributed to Matsuzaki, F..

10 recordsLinked to original sources

bioRxiv2025

Epigenetic-metabolic axis in the temporal scaling of mammalian cortical neurogenesis across species

Developmental timescales vary widely across species, with mammalian cortical neurogenesis ranging from just days to several months. Given the conserved laminar architecture and regulatory gene expression sequences, the underlying molecular mechanisms controlling neurogenesis rate remain unknown. Using mouse, ferret, and human models, we combined comparative transcriptomics with mathematical modelling to identify conditions that scale temporal gene expression programs during neurogenesis. We show that H3K27me3-mediated repression is critical for maintaining species-specific neurogenesis timescales, and its ablation scales down neurogenesis duration. Furthermore, we identified the tricarboxylic-acid (TCA)-cycle metabolite -ketoglutarate as a modulator of developmental timing via H3K27me3 demethylation. Together, our findings link epigenetic and metabolic states to the control of species-specific developmental timescales and, ultimately, brain size.

developmental biology↗

bioRxiv2024

Neuron-derived Prox1 suppresses injury-induced reprogramming of Muller glia to proliferative retinal progenitor cells

Individuals with retinal degenerative diseases face significant obstacles in restoring normal vision due to the inability to regenerate degenerated retinal cells. While retinal neurons can be regenerated from Muller glia (MG) in cold-blooded vertebrates, this regenerative ability is lacking in mammals, indicating the limited competence of mammalian MG for retinal regeneration. In this study, we elucidate the role of prospero-related homeobox 1 (Prox1) in rendering the mammalian retina incompetent for MG-derived regeneration. Prox1 accumulates in MG in the degenerating human and mouse retinas but not in those in the regenerating zebrafish retina. Strikingly, Prox1 in mouse MG originated from neighboring retinal neurons through intercellular protein transfer. Consequently, inhibition of Prox1 transfer to MG enables the reprogramming of MG into proliferative retinal progenitor cells in injured mouse retinas. Furthermore, we succeeded in regenerating retinal neurons and delaying vision loss in retinitis pigmentosa disease model in mice by adenoassociated viral gene delivery of an anti-Prox1 antibody that sequesters extracellular Prox1 in the mouse retina. Taken together, our findings highlight the therapeutic potential of anti-Prox1 therapy in restoring the regenerative potential of the mammalian retina.

developmental biology↗

bioRxiv2023

Efficient workflow for validating homology-independent targeted integration-mediated gene insertion in rod photoreceptor cells to treat dominant-negative mutations causing retinitis pigmentosa

Among the genome-editing methods for repairing disease-causing mutations resulting in dominant inhibition, homology-independent targeted integration (HITI)-mediated gene insertion of the normal form of the causative gene is useful because it allows the development of mutation-agnostic therapeutic products. For the rapid optimization and validation of highly effective HITI-treatment gene constructs against dominant-negative inheritance of inherited retinal dystrophy, we improved the gene constructs available in both plasmid and adeno-associated virus (AAV) vectors, and established a workflow that uses in vivo electroporation to verify the in vivo efficacy. By targeting the mouse Rhodopsin gene, we derived a construct in which HITI-mediated gene insertion occurs in 80%-90% of transduced mouse rod photoreceptor cells. This construct suppressed degeneration and induced visual restoration in the mutant mice. The HITI-treatment constructs for the rhodopsin gene were shown to be effective in AAV vectors, and this construction is available for the mouse Peripherin 2 gene. These findings suggest that the workflow reported here may be useful for the generation of HITI-treatment constructs for various target genes and for the development of gene therapy products.

molecular biology↗

bioRxiv2022

Deep embedded clustering by relevant scales and genome-wide association study in autism

The etiology of autism spectrum disorders (ASD) remains unclear. Stratifying patients with ASD may help to identify genetically homogeneous subgroups. Using a deep embedded clustering algorithm, we conducted cluster analyses of Simons Foundation Powering Autism Research for Knowledge (SPARK) datasets and performed genome-wide association studies (GWAS) of the clusters. We observed no significant associations in the conventional GWAS comparing all patients to all controls. However, in the GWAS, comparing patients divided into clusters with similar phenotypes to controls (cluster-based GWAS), we identified 90 chromosomal loci that satisfied the P < 5.0 x 10-8, several of which were located within or near previously reported candidate genes for ASD. Our findings suggest that clustering may successfully identify subgroups with relatively homogeneous disease etiologies.

genomics↗

bioRxiv2022

A novel Wnt pathway orients Par complex-dependent cell polarity

The Par-complex is a highly conserved cell polarization machinery, playing critical roles in tissue development and homeostasis. However, how extracellular signals globally orient Par-dependent cell polarity in tissues remains poorly understood. We show here that four of seven Drosophila Wnts redundantly serve as directional cues for the Par-dependent cell polarity of neural stem cells, neuroblasts, through a novel pathway. Wnt2/5/6/D proteins, expressed in ectodermal cells, act via frizzled receptors on underlying neuroblasts to localize armadillo/{beta}-catenin to neuroblast cytocortex facing the Wnt signal source. The localized armadillo recruits the Par complex and Pins complex to the neuroblast apical side, through the association of arm with Par3 and Inscuteable. Wnts consequently orient the cell polarity and asymmetric divisions of neuroblasts perpendicular to the epithelium, allowing nerve tissue to grow inward along the central-peripheral axis in Drosophila embryos. This novel non-canonical Wnt signaling pathway may regulate Par-dependent polarity in various biological contexts.

cell biology↗

bioRxiv2022

Single cell transcriptomics of ferrets reveal a common temporal pattern of progenitors in brain development of gyrencephalic mammals

The diversity of neural stem cells is a hallmark of the cerebral cortex development in gyrencephalic mammals, such as Primates and Carnivora. Among them, ferrets are a good model for mechanistic studies. However, information on their neural progenitor cells (NPC), termed radial glia (RG), is limited. Here, we surveyed the temporal series of single-cell transcriptomes of progenitors regarding ferret corticogenesis and, found a conserved diversity and temporal trajectory between human and ferret NPC, despite the large timescale difference. We found truncated RG (tRG) in ferret cortical development, a progenitor subtype previously described in humans. The combination of in silico and in vivo analyses identified that tRG differentiate into both ependymal and astrogenic cells. Via transcriptomic comparison, we predict that this is also the case in humans. Our findings suggest that tRG plays a role in the formation of adult ventricles, thereby providing the architectural bases for brain expansion.

developmental biology↗

bioRxiv2022

The cardiopharyngeal mesoderm contributes to lymphatic vessel development

Lymphatic vessels are crucial for tissue homeostasis and immune responses in vertebrates. Recent studies have demonstrated that lymphatic endothelial cells (LECs) arise from both venous sprouting (lymphangiogenesis) and de novo production from non-venous origins (lymphvasculogenesis), which is similar to blood vessel formation through angiogenesis and vasculogenesis. However, the contribution of LECs from non-venous origins to lymphatic networks is considered to be relatively small. Here, we identify the Islet1 (Isl1)-expressing cardiopharyngeal mesoderm (CPM) as a non-venous origin of craniofacial and cardiac LECs. Genetic lineage tracing with Isl1-Cre and Isl1-MerCreMer mice suggested that a subset of CPM cells gives rise to LECs. These CPM-derived LECs are distinct from venous-derived LECs in terms of their developmental processes and anatomical locations. Later, they form the craniofacial and cardiac lymphatic vascular networks in collaboration with venous-derived LECs. Collectively, our results demonstrate that there are two major sources of LECs, the cardinal vein and the CPM. As the CPM is evolutionarily conserved, these findings may improve our understanding of the evolution of lymphatic vessel development across species. Most importantly, our findings may provide clues to the pathogenesis of lymphatic malformations, which most often develop in the craniofacial and mediastinal regions.

developmental biology↗

bioRxiv2020

Selective translation of epigenetic modifiers drives the developmental clock of neural stem cells

The cerebral cortex is formed by diverse neurons generated sequentially from neural stem cells (NSCs). A clock mechanism has been suggested to underlie the temporal progression of NSCs, which is mainly defined by the transcriptome and the epigenetic state. However, what drives such a developmental clock remains elusive. We show that translational control of histone H3 trimethylation at Lys27 (H3K27me3) modifiers is part of this clock. We found that depletion of Fbl, an rRNA methyltransferase, reduces translation of both the Ezh2 methyltransferase and Kdm6b demethylase of H3K27me3 and delays progression of the NSC state. These defects are phenocopied by simultaneous inhibition of H3K27me3 methyltransferase and demethylase, indicating the role of Fbl in the genome-wide H3K27me3 pattern. Fbl selectively enhances the translation of H3K27me3 modifiers via a cap-independent mechanism. We thus propose that Fbl drives the intrinsic clock through the translational enhancement of H3K27me3 modifiers that predominantly define the NSC state.

developmental biology↗

bioRxiv2019

Shear forces drive precise patterning of hair cells in the mammalian inner ear

Precise cellular organizations are required for the function of many organs and tissues. It is often unclear, however, how such precise patterns emerge during development. The mammalian hearing organ, the organ of Corti, consists of a remarkably organized pattern of four rows of hair cells (HCs) interspersed by non-sensory supporting cells (SCs). This checkerboard-like pattern of HCs and SCs emerges from a disordered epithelium over several days, yet the transition to an ordered cellular pattern is not well understood. Using a combination of quantitative morphological analysis and time-lapse imaging of mouse cochlear explants, we show here that patterning of the organ of Corti involves dynamic reorganizations that include lateral shear motion, cell intercalations, and delaminations. A mathematical model, where tissue morphology is described in terms of the mechanical forces that act on cells and cellular junctions, suggests that global shear on HCs and local repulsion between HCs are sufficient to drive the tissue into the final checkerboard-like pattern. Our findings suggest that precise patterns can emerge during development from reorganization processes, driven by a combination of global and local forces in a process analogous to shear-induced crystallization.

developmental biology↗

bioRxiv2019

Reconstruction of Par polarity in apolar cells reveals a dynamic process of cortical polarization

Cellular polarization is fundamental for various biological processes. The Par network system is conserved for cellular polarization. Its core complex consists of Par3, Par6, and aPKC. However, the dynamic processes that occur during polarization are not well understood. Here, we artificially reconstructed Par-dependent polarity using non-polarized Drosophila S2 cells expressing all three components endogenously in the cytoplasm. The results indicated that elevated Par3 expression induces cortical localization of the Par-complex at the interphase. Its asymmetric distribution goes through three steps: emergence of cortical dots, development of island-like structures with dynamic amorphous shapes, repeating fusion and fission, and polarized clustering of the islands. Our findings also showed that these islands contain a meshwork of unit-like segments. Par-complex patches resembling Par-islands exist in Drosophila mitotic neuroblasts. Thus, this reconstruction system provides an experimental paradigm to study features of the assembly process and structure of Par-dependent cell-autonomous polarity.

cell biology↗