Endosomal trafficking defects cause microcephaly
A large number of genetic causes for cortical malformations remain undiscovered. We have established a close collaboration with Nadia Bahi-Buisson (PU-PH, Necker-Enfants maladies & Imagine Institute) who works on identifying novel mutations using the latest developments in omics methods. Our goal is to identify the molecular functions of identified factors during neocortex development, and the basis of the pathological alterations. We identified human mutations leading to severe microcephaly in WDR81, a gene coding for a regulator of endosomal maturation (Cavallin et al., Brain, 2017). To identify the function of WDR81 in the developing neocortex, we generated a KO mouse, which displayed microcephaly and altered neuronal positioning, phenocopying the human disease (Carpentieri et al, Nat Comm, 2022). Mechanistically, we showed that WDR81 loss of function alters endosomal trafficking of the EGF receptor, leading to reduced MAPK activation, reduced RG proliferation and, as a consequence, microcephaly. As microcephaly is largely linked to apoptotic cell death, this was a striking example of reduced brain size being a direct consequence of progenitor proliferation defects. Interestingly, megalencephaly (enlarged brain) has been described to arise from overproliferation of the progenitor pool. Accordingly, we were able to rescue the WDR81-/- proliferation defects with a megalencephaly-causing mutated form of Cyclin D2, indicating that microcephaly and megalencephaly can be viewed as two sides of the same coin.
© Team BAFFET
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WDR81 KO mice display reduced brain size and altered neuronal positioning A. WDR81-/- postnatal day 7 brains are microcephalic and display reduced cortical surface area as compared to WT brains. B. Quantification of hemisphere area at P7 in WT and WDR81 KO1 brains. C. DAPI staining of P7 WT and WDR81-/- cross sections reveals reduced cortical thickness in mutants. D. Quantification of cortical thickness in WT, KO1 and KO2 brains at P0 and P7. E. NeuN staining of WT and WDR81-/- cortical plates (CP) at P0. F. Quantification of NEUN+ cells in WT and WDR81 KO1 cortical plates at P0 in 600x300 𝜇m crops reveals reduced number of neurons at birth. |
Carpentieri JA, Di Cicco A, Andreau D, Del Maestro L, El Marjou F, Coquand L, Bahi-Buisson N, Brault JB, Baffet AD. (2022) Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly. Nat Commun. Jan 10;13(1):16
© Team BAFFET