PubMed · 15882631
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Gord Fishell, Arnold Kriegstein. 2005-05-05. Cortical development: new concepts.. https://doi.org/10.1016/j.neuron.2005.04.016
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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.
BACKGROUND: John Hughlings Jackson (1835-1911) in London was critical in advancing the concept of cerebral localization. Hughlings Jackson, however, did not work in a vacuum. Silas Weir Mitchell (1829-1914), in Philadelphia, published several clinical observations related to localization. OBJECTIVE: To examine Weir Mitchell's clinical observations on sensory localization, to determine whether they influenced Jacksonian neurology, and to elucidate the private relationship between the two men. METHODS: The authors reviewed published (fictional and scientific writings of Weir Mitchell and scientific writings of Hughlings Jackson) and archival sources (Weir Mitchell's unpublished autobiography and Hughlings Jackson's unpublished correspondence with Weir Mitchell). RESULTS: In the 1860s, Weir Mitchell, through his work on phantom limb syndrome and other nerve injuries, made oblique references to the central representation of body parts, specifically with regard to sensation. Hughlings Jackson had an interest in somatotopic representation in the nervous system and repeatedly cited Weir Mitchell's work in support of his ideas. The two shared several patients, met at least once in London, and carried on a friendly correspondence. CONCLUSIONS: Weir Mitchell's observations on sensory localization were well known to Hughlings Jackson, who cited them in seminal articles on cortical localization. Their correspondence provides an example of trans-Atlantic scientific and clinical communication at the time that neurology emerged as a distinct clinical discipline.
The cerebral cortex is a remarkably homogeneous structure suggesting a rather generic computational machinery. Indeed, under a variety of conditions, functions attributed to specialized areas can be supported by other regions. However, a host of studies have laid out an ever more detailed map of functional cortical areas. This leaves us with the puzzle of whether different cortical areas are intrinsically specialized, or whether they differ mostly by their position in the processing hierarchy and their inputs but apply the same computational principles. Here we show that the computational principle of optimal stability of sensory representations combined with local memory gives rise to a hierarchy of processing stages resembling the ventral visual pathway when it is exposed to continuous natural stimuli. Early processing stages show receptive fields similar to those observed in the primary visual cortex. Subsequent stages are selective for increasingly complex configurations of local features, as observed in higher visual areas. The last stage of the model displays place fields as observed in entorhinal cortex and hippocampus. The results suggest that functionally heterogeneous cortical areas can be generated by only a few computational principles and highlight the importance of the variability of the input signals in forming functional specialization.