PubMed · 12672314
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Philip E M Smith, Pushkar Shah, Jan Sharpe, Anna Todd, Andrew P Goringe. 2003-03-29. Palinopsia.. https://doi.org/10.1016/s0140-6736(03)12896-6
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DNA packaging into heterochromatin is a fundamental mechanism of transcriptional silencing, yet its role in regulating neural progenitor behavior during brain development remains poorly understood. Trimethylation of histone H3 lysine 9 (H3K9me3), catalyzed by the methyltransferases SETDB1, SUV39H1, and SUV39H2, is a defining feature of heterochromatin, but functional redundancy among these enzymes has obscured their developmental roles. Here, we generated a cortex-specific triple knockout mouse model lacking Setdb1, Suv39h1, and Suv39h2 to directly interrogate H3K9me3 function during corticogenesis. Combined loss of H3K9 methyltransferases caused genome-wide depletion of H3K9me3, disruption of neural progenitor cell-cycle progression, and impaired cortical neurogenesis, resulting in microcephaly. H3K9 methyltransferases preserve neural progenitor identity and function by silencing clustered protocadherins, meiosis-associated genes, and a cell-cycle restraint program through H3K9me3 deposition. Loss of H3K9me3 promoted local chromatin opening and increased transcription factor occupancy, enabling transposable elements to acquire cryptic enhancer activity and modulate proximal gene expression. Together, these findings establish H3K9me3 heterochromatin as an active regulator of neural progenitor dynamics and lineage fidelity, revealing a central epigenetic mechanism that restricts aberrant transcriptional programs to ensure cortical growth.
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Penetration depth is investigated in terms of the performance of transverse image resolution and signal level in human cortex under single-, two-, and three-photon fluorescence microscopy. Simulation results show that, in a double-layer human cortex structure consisting of gray and white matter media, the signal level is strongly affected by the existence of the white matter medium under three-photon excitation. Compared with three-photon excitation, two-photon excitation keeps a better signal level and sacrifices a slight degradation in image resolution. In a thick gray matter medium, a penetration depth of 1500 microm with a near-diffraction-limited resolution is obtainable under three-photon excitation. It is also demonstrated that the numerical aperture has a slight influence on image resolution and signal level under two- and three-photon excitation because of the nonlinear nature in the excitation process.