Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Mutations in chromatin modifier genes are linked to neurodevelopmental disorders.
• Chromodomain helicase DNA-binding protein 7 (Chd7) is associated with CHARGE syndrome.

Purpose of the Study:

• To investigate the role of Chd7 in cerebellar development.
• To elucidate the molecular mechanisms underlying Chd7-dependent cerebellar development.

Main Methods:

• Genetic inactivation of Chd7 in mouse cerebellar granule neuron progenitors.
• Molecular analyses including chromatin accessibility and gene expression studies.

Main Results:

• Chd7 inactivation led to cerebellar hypoplasia, impaired granule neuron differentiation, increased apoptosis, and abnormal Purkinje cell localization in mice.
• Chd7 maintains open chromatin and activates genes crucial for granule neuron differentiation.
• Chd7 and Top2b are both required for the transcription of long neuronal genes.

Conclusions:

• Chd7 is indispensable for normal cerebellar development.
• Chd7 acts by maintaining chromatin accessibility and regulating a core transcriptional program for neuronal differentiation.
• These findings provide insights into the pathogenesis of CHARGE syndrome and the role of chromatin remodelers in brain development.