PubMed · 12483850
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Nobutaka Arai. 2002. [Microdysgenesis].. https://pubmed.ncbi.nlm.nih.gov/12483850/
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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.
We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.
OBJECTIVE: To test the hypothesis that postural imbalance after stroke may be caused by inability to use pertinent somatosensory, vestibular, or visual information. DESIGN: Description of the sensory organization of patients with hemiplegia. SETTING: Public rehabilitation center in France. PARTICIPANTS: Forty patients with hemiplegia after a single hemisphere stroke who were at least 12 months post stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The patients performed computerized dynamic posturography (EquiTest), which is designed to assess a patient's ability use sensory inputs separately and to effectively suppress inaccurate inputs in case of sensory conflict. Body stability under each of 6 sensory conditions was assessed by an equilibrium score (ES). RESULTS: In conditions of altered somatosensory information, with visual deprivation (ES5) or visuovestibular conflict (ES6), the median scores for patients with hemiplegia (ES5-43; ES6-20) were significantly lower than those for normal subjects (ES5-69; ES6-67). CONCLUSIONS: Many patients with hemiplegia seem to rely on visual input. The mechanism of this excessive visual reliance is discussed. Rehabilitation programs of postural control for the patients with hemiplegia should take into account the possible impairment of sensory organization and should include exercises to be performed under conditions of sensory input deprivation and sensory conflict.