Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

Area of Science:

• Neuroscience
• Developmental Biology
• Cell Biology

Background:

• Primary microcephaly (reduced brain size) and megalencephaly (increased brain size) are severe brain malformations.
• Microcephaly is often linked to centrosomal defects, but the molecular basis for both conditions remains unclear.

Purpose of the Study:

• Investigate the role of WDR81 in brain development, as its loss causes microcephaly.
• Determine the molecular mechanisms underlying WDR81-associated microcephaly and its potential link to megalencephaly.

Main Methods:

• Studied WDR81 loss-of-function in patient-derived microcephaly.
• Analyzed WDR81's role in endosomal trafficking of EGFR and MAP kinase pathway activation.
• Examined proliferation rates of WDR81-deficient mouse radial glial progenitor cells.
• Utilized Cyclin D2 mutants to assess rescue effects in vivo.

Main Results:

• WDR81 loss impairs endosomal EGFR trafficking and reduces MAP kinase pathway activation.
• WDR81-deficient radial glial progenitor cells show decreased proliferation, leading to reduced brain size.
• Megencephaly-associated Cyclin D2 mutants rescued the proliferation defects in vivo.

Conclusions:

• WDR81 is crucial for regulating radial glial progenitor proliferation and brain growth via endosomal trafficking.
• Opposite alterations in radial glial progenitor proliferation can explain both microcephaly and megalencephaly.
• The endosomal machinery is identified as a key regulator of brain size determination.