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Published on: August 16, 2020
DSCAM regulates delamination of neurons in the developing midbrain
Nariko Arimura1, Mako Okada2,3, Shinichiro Taya2
1Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. n-arimur@ncnp.go.jp hoshino@ncnp.go.jp.
Abstract:
For normal neurogenesis and circuit formation, delamination of differentiating neurons from the proliferative zone must be precisely controlled; however, the regulatory mechanisms underlying cell attachment are poorly understood. Here, we show that Down syndrome cell adhesion molecule (DSCAM) controls neuronal delamination by local suppression of the RapGEF2-Rap1-N-cadherin cascade at the apical endfeet in the dorsal midbrain. Dscam transcripts were expressed in differentiating neurons, and DSCAM protein accumulated at the distal part of the apical endfeet. Cre-loxP-based neuronal labeling revealed that Dscam knockdown impaired endfeet detachment from ventricles. DSCAM associated with RapGEF2 to inactivate Rap1, whose activity is required for membrane localization of N-cadherin. Correspondingly, Dscam knockdown increased N-cadherin localization and ventricular attachment area at the endfeet. Furthermore, excessive endfeet attachment by Dscam knockdown was restored by co-knockdown of RapGEF2 or N-cadherin Our findings shed light on the molecular mechanism that regulates a critical step in early neuronal development.
Insights
Down syndrome cell adhesion molecule (DSCAM) regulates neuronal delamination by controlling cell attachment. This finding reveals a key mechanism in early brain development and neurogenesis.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Precise control of neuronal delamination is crucial for normal neurogenesis and brain circuit formation.
- The molecular mechanisms governing cell attachment during neuronal delamination are not well understood.
Purpose of the Study:
- To investigate the role of Down syndrome cell adhesion molecule (DSCAM) in regulating neuronal delamination.
- To elucidate the molecular pathway through which DSCAM controls cell attachment at the apical endfeet.
Main Methods:
- Utilized Cre-loxP-based neuronal labeling in the dorsal midbrain.
- Investigated DSCAM expression and localization in differentiating neurons.
- Analyzed the interaction between DSCAM, RapGEF2, Rap1, and N-cadherin.
Main Results:
- Down syndrome cell adhesion molecule (DSCAM) knockdown impaired neuronal endfeet detachment from ventricles.
- DSCAM associates with RapGEF2 to suppress the Rap1-N-cadherin cascade, controlling cell adhesion.
- Increased N-cadherin localization and attachment area were observed upon DSCAM knockdown, which was rescued by RapGEF2 or N-cadherin co-knockdown.
Conclusions:
- DSCAM plays a critical role in regulating neuronal delamination by suppressing the RapGEF2-Rap1-N-cadherin pathway at apical endfeet.
- This study reveals a novel molecular mechanism controlling a vital step in early neuronal development.
- Understanding DSCAM's function provides insights into neurogenesis and potential therapeutic targets.
