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Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex
Published on: June 4, 2014
Csk-dependent and -independent control of Src family kinases directs neuronal migration in the developing cerebral
Yoshiaki V Nishimura1, Shiho Ito2, Takeshi Kawauchi3
1Division of Neuroscience, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
Abstract:
Fyn, a proto-oncogene product of Src family kinases (SFKs), plays pivotal roles in various pathological and physiological events, including cancer and immunity. C-terminal Src kinase (Csk) is a negative regulator for all SFKs, including Fyn, and acts as a tumor suppressor, but its involvement in normal tissue morphogenesis remains unclear. Here, we show that Csk plays essential roles in cerebral cortical development. In vivo knockdown of Csk, as well as constitutive active form of Fyn (CA-Fyn), disturbs neuronal migration and immature neurite formation without affecting neural progenitor proliferation and neuronal differentiation in the developing cerebral cortex. Although overactivation of SFKs is known to downregulate cadherin-mediated cell-to-cell adhesion, both Csk knockdown and CA-Fyn promote attachments between immature neurons. Interestingly, CA-Fyn, but not Csk knockdown, increases N-cadherin cell surface levels. Csk knockdown upregulates SFK activities near the plasma membrane, but not in total cell lysates, whereas CA-Fyn promotes both, implying a Csk-independent role of cytosolic Fyn in N-cadherin plasma membrane localization. In contrast, Csk knockdown and CA-Fyn commonly promote cell surface levels of L1-CAM, an immunoglobulin superfamily cell adhesion molecule that controls cortical neuronal migration. Thus, Csk-mediated local regulation of membrane-bound SFK activities appears essential for cortical neuronal migration through fine-tuning of intercellular attachment strength between immature neurons.
Insights
C-terminal Src kinase (Csk) is crucial for cerebral cortical development, regulating neuronal migration and neurite formation. Its localized activity fine-tunes cell adhesion, essential for proper brain development.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Proto-oncogene product Fyn (a Src family kinase, SFK) is involved in cancer and immunity.
- C-terminal Src kinase (Csk) negatively regulates SFKs and acts as a tumor suppressor.
- Csk's role in normal tissue morphogenesis, particularly brain development, is largely unknown.
Purpose of the Study:
- To investigate the role of Csk in cerebral cortical development.
- To elucidate the mechanisms by which Csk and Fyn influence neuronal migration and neurite formation.
Main Methods:
- In vivo knockdown of Csk in the developing cerebral cortex.
- Expression of a constitutively active form of Fyn (CA-Fyn).
- Analysis of neuronal migration, neurite formation, proliferation, differentiation, and cell adhesion molecule expression (N-cadherin, L1-CAM).
- Assessment of Src family kinase activity at the plasma membrane and in total cell lysates.
Main Results:
- Csk knockdown and CA-Fyn expression disrupt neuronal migration and immature neurite formation.
- Both Csk knockdown and CA-Fyn promote cell-to-cell attachments between immature neurons.
- Csk knockdown enhances SFK activity near the plasma membrane, while CA-Fyn increases it globally.
- Both Csk knockdown and CA-Fyn increase cell surface levels of L1-CAM, a key molecule for cortical neuronal migration.
Conclusions:
- Csk plays an essential role in cerebral cortical development.
- Csk-mediated local regulation of SFK activity is critical for neuronal migration.
- Fine-tuning of intercellular adhesion strength by Csk is vital for proper cortical development.
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