The microtubule-binding protein EML3 is required for mammalian embryonic growth and cerebral cortical development; Eml3 null mice are a model of cobblestone brain malformation

Carrier, I.; Diez, E.; Piscopo, V. E. C.; Bechstedt, S.; van Bokhoven, H.; Srour, M.; Berghuis, A.; Stifani, S.; Yamanaka, Y.; McInnes, R. R.

doi:10.1101/2025.04.06.647459

bioRxiv · 10.1101/2025.04.06.647459

The microtubule-binding protein EML3 is required for mammalian embryonic growth and cerebral cortical development; Eml3 null mice are a model of cobblestone brain malformation

Carrier, I.·Diez, E.·Piscopo, V. E. C.·Bechstedt, S.·van Bokhoven, H.·Srour, M.·Berghuis, A.·Stifani, S.·Yamanaka, Y.·McInnes, R. R.

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Abstract

The cerebral cortex is a multi-layered structure generated through the migration of neural precursors from their birthplace in the ventricular zone to their destination within the cortical plate. Neuronal migration defects are responsible for many human pathologies collectively called neuronal migration disorders, which include subcortical band heterotopia and cobblestone brain (COB) malformation. One example of a protein involved in a neuronal migration disorder is the echinoderm microtubule-associated protein-like 1 (EML1) protein, one of six members of the mammalian EML family. Absence of EML1 protein results in subcortical band heterotopia in mice and humans. Here, we report that absence of the paralogous protein EML3 leads to delayed embryonic development and small size, and a COB-like phenotype with neuronal ectopias in the dorsal telencephalon. We found that EML3 is expressed in the neuroepithelium and meningeal mesenchyme when those tissues participate in pial basement membrane (PBM) formation. Transmission electron microscopy demonstrated that the extracellular matrix of the PBM is structurally abnormal in Eml3 null mice when the first radially migrating neurons arrive. The reduced structural integrity of the PBM leads to focal over-migration of neurons into the subarachnoid space. These findings strengthen the link between the EML protein family and cortical neuronal migration defects by identifying Eml3 as the first EML family member whose absence leads to over-migration of neuroblasts. Moreover, we report the first COB-like phenotype with PBM structural defects when a single microtubule-associated protein is deleted.

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Carrier, I., Diez, E., Piscopo, V. E. C., Bechstedt, S., van Bokhoven, H., Srour, M., Berghuis, A., Stifani, S., Yamanaka, Y., McInnes, R. R.. 2025-04-06. The microtubule-binding protein EML3 is required for mammalian embryonic growth and cerebral cortical development; Eml3 null mice are a model of cobblestone brain malformation. https://doi.org/10.1101/2025.04.06.647459

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