The chromatin remodeling factor CHD7 controls cerebellar development by regulating reelin expression

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• CHARGE syndrome involves neurodevelopmental deficits like cerebellar hypoplasia and developmental delay.
• Mutations in the ATP-dependent chromatin remodeler CHD7 are linked to CHARGE syndrome.
• The role of CHD7 in neurogenesis during brain development is largely unknown.

Purpose of the Study:

• To investigate the role of CHD7 in cerebellar development and neurogenesis.
• To identify the molecular mechanisms by which CHD7 influences brain development.
• To explore the link between CHD7, Reelin (Reln) expression, and cerebellar hypoplasia.

Main Methods:

• Deletion of Chd7 in mouse cerebellar granule cell progenitors (GCps).
• Genome-wide expression profiling to identify altered gene expression.
• Molecular and genetic analyses to assess the contribution of Reelin (Reln).
• Chromatin accessibility assays at the Reln locus.

Main Results:

• Chd7 deletion in GCps caused reduced proliferation, cerebellar hypoplasia, developmental delay, and motor deficits in mice.
• Downregulated Reelin (Reln) expression was observed in Chd7-deficient GCps.
• Evidence suggests reduced Reln expression contributes to GCp defects and cerebellar hypoplasia.
• CHD7 is essential for maintaining an open chromatin state at the Reln locus.

Conclusions:

• Reelin (Reln) gene expression is regulated by chromatin remodeling.
• CHD7 is a novel upstream regulator of Reelin (Reln) in brain development.
• Mammalian CHD proteins control brain development by modulating chromatin accessibility in neuronal progenitors.