| 1. |
Sayako Katada,Jun Takouda,Takumi Nakagawa,Mizuki Honda,Katsuhide Igarashi,
Takuya Imamura,Yasuyuki Ohkawa,Shoko Sato,Hitoshi Kurumizaka,Kinichi Nakashima, Neural stem/precursor cells dynamically change their epigenetic landscape to differentially respond to BMP signaling for fate switching during brain development, Genes Dev, 10.1101/gad.348797.121., 35, 1431-1444, 2021.11, During neocortical development, tight regulation of neurogenesis-to-astrogenesis switching of neural precursor cells
(NPCs) is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating
evidence indicates that a complex array of epigenetic modifications and the availability of extracellular factors
control the timing of neuronal and astrocytic differentiation. However, our understanding of NPC fate regulation is
still far from complete. Bone morphogenetic proteins (BMPs) are renowned as cytokines that induce astrogenesis of
gliogenic late-gestational NPCs. They also promote neurogenesis of mid-gestational NPCs, although the underlying
mechanisms remain elusive. By performing multiple genome-wide analyses, we demonstrate that Smads, transcription
factors that act downstream from BMP signaling, target dramatically different genomic regions in neurogenic
and gliogenic NPCs. We found that histone H3K27 trimethylation and DNA methylation around Smadbinding
sites change rapidly as gestation proceeds, strongly associated with the alteration of accessibility of Smads to
their target binding sites. Furthermore, we identified two lineage-specific Smad-interacting partners—Sox11 for
neurogenic and Sox8 for astrocytic differentiation—that further ensure Smad-regulated fate-specific gene induction.
Our findings illuminate an exquisite regulation of NPC property change mediated by the interplay between
cell-extrinsic cues and -intrinsic epigenetic programs during cortical development.. |
| 2. |
Doi, H.
Matsuda, T.
Sakai, A.
Matsubara, S.
Hoka, S.
Yamaura, K.
Nakashima, K., Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition, Proc Natl Acad Sci USA, 10.1073/pnas.2107596118, 118, 38, 2021.09, We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFkappaB activation as well as increased PTPN3 expression. NFkappaB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFkappaB enhanced PTPN3 expression and tyrosine kinase activation. TGFbeta reduced PTPN3 expression and NFkappaB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.. |
| 3. |
Nakashima, H.
Tsujimura, K.
Irie, K.
Imamura, T.
Trujillo, C. A.
Ishizu, M.
Uesaka, M.
Pan, M.
Noguchi, H.
Okada, K.
Aoyagi, K.
Andoh-Noda, T.
Okano, H.
Muotri, A. R.
Nakashima, K., MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling, Cell Reports, 10.1016/j.celrep.2021.109124, 35, 7, 2021.05, Rett syndrome (RTT) is a severe neurological disorder, with impaired brain development caused by mutations in MECP2; however, the underlying mechanism remains elusive. We know from previous work that MeCP2 facilitates the processing of a specific microRNA, miR-199a, by associating with the Drosha complex to regulate neuronal functions. Here, we show that the MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation. A shift occurs from neuronal to astrocytic differentiation of MeCP2- and miR-199a-deficient NS/PCs due to the upregulation of a miR-199a target, Smad1, a downstream transcription factor of bone morphogenetic protein (BMP) signaling. Moreover, miR-199a expression and treatment with BMP inhibitors rectify the differentiation of RTT patient-derived NS/PCs and development of brain organoids, respectively, suggesting that facilitation of BMP signaling accounts for the impaired RTT brain development. Our study illuminates the molecular pathology of RTT and reveals the MeCP2/miR-199a/Smad1 axis as a potential therapeutic target for RTT.. |
