Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo | Acta Neuropathologica Communications | Full Text

Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo | Acta Neuropathologica Communications | Full Text

Acta Neuropathologica Communications

Dynein activating adaptor BICD2 controls radial migration of upper-layer cortical neurons in vivo

• Lena Will, 
• Sybren Portegies, 
• Jasper van Schelt, 
• Merel van Luyk, 
• Dick Jaarsma & 
• Casper C. Hoogenraad 

Acta Neuropathologica Communications volume 7, Article number: 162 (2019) | Download Citation

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Abstract

For the proper organization of the six-layered mammalian neocortex it is required that neurons migrate radially from their place of birth towards their designated destination. The molecular machinery underlying this neuronal migration is still poorly understood. The dynein-adaptor protein BICD2 is associated with a spectrum of human neurological diseases, including malformations of cortical development. Previous studies have shown that knockdown of BICD2 interferes with interkinetic nuclear migration in radial glial progenitor cells, and that Bicd2-deficient mice display an altered laminar organization of the cerebellum and the neocortex. However, the precise in vivo role of BICD2 in neocortical development remains unclear. By comparing cell-type specific conditional Bicd2 knock-out mice, we found that radial migration in the cortex predominantly depends on BICD2 function in post-mitotic neurons. Neuron-specific Bicd2 cKO mice showed severely impaired radial migration of late-born upper-layer neurons. BICD2 depletion in cortical neurons interfered with proper Golgi organization, and neuronal maturation and survival of cortical plate neurons. Single-neuron labeling revealed a specific role of BICD2 in bipolar locomotion. Rescue experiments with wildtype and disease-related mutant BICD2 constructs revealed that a point-mutation in the RAB6/RANBP2-binding-domain, associated with cortical malformation in patients, fails to restore proper cortical neuron migration. Together, these findings demonstrate a novel, cell-intrinsic role of BICD2 in cortical neuron migration in vivo and provide new insights into BICD2-dependent dynein-mediated functions during cortical development.

Highlights

• Neuron-specific conditional Bicd2 knockout mice show severe cortical neuronal migration defects
• Cell-intrinsic function of BICD2 is essential for nuclear migration during locomotion of upper-layer neurons, neuronal maturation and survival
• Mutant BICD2, associated with cortical malformation in patients, fails to rescue neuron-specific migration defects
• Glia-specific loss of BICD2 affects tempo-spatial regulation of RGP mitosis