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Published on: April 14, 2017
Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly
Jacopo A Carpentieri1, Amandine Di Cicco1, Marusa Lampic1
1Institut Curie, PSL Research University, CNRS UMR144, 75005, Paris, France.
Abstract:
Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors.
Insights
WDR81 loss causes microcephaly by impairing cell proliferation. Opposite effects on proliferation explain both microcephaly and megalencephaly, linking endosomal trafficking to brain growth regulation.
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.
