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Friday Science Review: April 27, 2012

All vertebrates share a general brain structure, featuring a forebrain, midbrain, and hindbrain, something that is most evident during embryogenesis. However, it is the size and structure of the forebrain and most notably the cerebral cortex that differentiates mammals from the other vertebrates.

As might be expected, the process by which the mammalian forebrain develops is a hugely complicated and fortunately tightly regulated process that involves the expansion of neural progenitor cells, followed by coordinated asymmetric divisions and differentiation to produce the specialized neuronal subtypes that make up the six layers of the cortex.

Regulation of this process is achieved through a combination of internal cellular programs and modulation by external signaling factors.  Neurogenic transcription factors were obvious actors in the intrinsic cellular programs, however, observations that mutations in genes encoding chromatin remodeling proteins caused neurodevelopmental disorders has implicated a role for epigenetics in brain development. It is to our understanding of this epigenetic mechanism to which researchers at the Ottawa Hospital Research Institute and the University of Ottawa have contributed with their recent paper in Developmental Cell.

They sought to determine the in vivo roles of the mammalian ISWI chromatin remodeling protein Snf2l in murine forebrain development by using a conditional targeting approach to remove Snf2I’s ATP-binding motif, thereby impairing its chromatin remodeling activity. Mice containing the mutated Snf2I showed enhanced neural progenitor cell expansion and forebrain hypercellularity that arose from an increased progenitor cell cycle rate and enhanced self-renewal. The hypercellularity was caused by perturbation of the progenitor cell cycle kinetics and delays in the initiation of differentiation and neurogenesis. Expression profiling of the mutant mice, identified increased expression of Foxg1/Brain factor-1, a forkhead homeodomain transcription factor, and the researchers were able to show that Snf2I’s normal role is to reduce Foxg1/Brain factor-1 expression, thereby resulting in the increase in activity of p21 and terminal differentiation of the progenitor cells.

Other Publications:

  • Structure of an intermediate state in protein folding and aggregation. Science. University of Toronto
  • Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. PLoS One. University of Toronto
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