FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.
Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity.
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.
Giorgio
G
La Fata
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.
Annette
A
Gärtner
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.
Nuria
N
Domínguez-Iturza
Biomedical MRI, KU Leuven, Leuven, Belgium.
Tom
T
Dresselaers
Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, the Netherlands.
Julia
J
Dawitz
Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, the Netherlands.
Rogier B
RB
Poorthuis
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.
Michele
M
Averna
Biomedical MRI, KU Leuven, Leuven, Belgium.
Uwe
U
Himmelreich
Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, the Netherlands.
Rhiannon M
RM
Meredith
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium.
Tilmann
T
Achsel
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium. [3] Centro de Biología Molecular Severo Ochoa, Campus de la Universidad Autónoma de Madrid, Spain.
Carlos G
CG
Dotti
1] VIB Center for the Biology of Disease, KU Leuven, Leuven, Belgium. [2] Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases (LIND), KU Leuven, Leuven, Belgium. [3] Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Claudia
C
Bagni
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D013003:Somatosensory Cortex / Q000166:cytology / Q000502:physiology*
D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse