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Caspr4 interaction with LNX2 modulates the proliferation and neuronal differentiation of mouse neural progenitor
Feng-Ting Yin1, Toshitaka Futagawa, Di Li
11 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University , Suzhou, China .
Abstract:
Contactin-associated protein 4 (Caspr4), also known as contactin-associated protein-like protein (CNTNAP4), is expressed in various regions of the brain. Recent reports suggest that CNTNAP4 is a susceptibility gene of autism spectrum disorders (ASDs). However, the molecular function of Caspr4 in the brain has yet to be identified. In this study, we show an essential role of Caspr4 in neural progenitor cells (NPCs). Caspr4 is expressed in NPCs in the subventricular zone (SVZ), a neurogenic region in the developing cortex. Knocking down of Caspr4 enhances the proliferation of NPCs derived from the SVZ of embryonic day 14 mouse. Neuronal differentiation is increased by overexpression of Caspr4, but decreased by knocking down of Caspr4 in cultured mouse NPCs. Transfection of the intracellular domain of Caspr4 (C4ICD) rescues the abnormal decreased neuronal differentiation of Caspr4-knocking down NPCs. Ligand of Numb protein X2 (LNX2), a binding partner of Numb, interacts with Caspr4 in a PDZ domain-dependent manner and plays a similar role to Caspr4 in NPCs. Moreover, transfection of LNX2 rescues the decreased neuronal differentiation in Caspr4-knocking down NPCs. In contrast, transfection of C4ICD fails to do so in LNX2-knocking down NPCs. These results indicate that Caspr4 inhibits neuronal differentiation in a LNX-dependent manner. Therefore, this study reveals a novel role of Caspr4 through LNX2 in NPCs, which may link to the pathogenesis of ASDs.
Insights
Contactin-associated protein 4 (Caspr4) plays a key role in neural progenitor cells, inhibiting neuronal differentiation via LNX2. This finding offers insights into autism spectrum disorder (ASD) pathogenesis.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Contactin-associated protein 4 (Caspr4/CNTNAP4) is implicated in autism spectrum disorders (ASDs).
- Its specific molecular function in the brain, particularly in neural progenitor cells (NPCs), remains largely unknown.
- Caspr4 is found in the subventricular zone (SVZ), a critical region for cortical development.
Purpose of the Study:
- To elucidate the molecular function of Caspr4 in neural progenitor cells.
- To investigate the role of Caspr4 in NPC proliferation and neuronal differentiation.
- To identify interacting partners and pathways involved in Caspr4's function.
Main Methods:
- Utilized mouse models to study Caspr4 expression and function in NPCs from the SVZ.
- Employed gene knockdown and overexpression techniques for Caspr4 and its intracellular domain (C4ICD).
- Investigated the interaction between Caspr4 and Ligand of Numb protein X2 (LNX2) using co-transfection and rescue experiments.
Main Results:
- Knocking down Caspr4 increased NPC proliferation but decreased neuronal differentiation.
- Overexpression of Caspr4 enhanced neuronal differentiation.
- Caspr4 interacts with LNX2 in a PDZ domain-dependent manner, and LNX2 plays a similar role in NPCs.
- LNX2 could rescue the decreased neuronal differentiation in Caspr4-knockdown NPCs, but C4ICD could not rescue LNX2-knockdown NPCs.
Conclusions:
- Caspr4 inhibits neuronal differentiation in NPCs through an LNX2-dependent mechanism.
- This study reveals a novel function of Caspr4 in NPCs, potentially linking it to the underlying mechanisms of ASDs.
- Caspr4's role in regulating neurogenesis may be a critical factor in neurodevelopmental disorders.
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