reelin-mediated signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by the binding of reelin (a secreted glycoprotein) to a receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:bf, PMID:12827279, PMID:20223215]

Reelin, a large extracellular glycoprotein secreted by Cajal-Retzius cells in the developing brain and some GABAergic interneurons in the mature brain, plays a critical role in neuronal migration, positioning, and dendritic development. It mediates its effects through a complex signaling pathway involving several key components:

1. **Reelin Receptor Binding:** Reelin binds to its receptors, ApoER2 (apolipoprotein E receptor 2) and VLDLR (very low-density lipoprotein receptor), which are transmembrane proteins expressed on the surface of neurons.

2. **Adaptor Protein Recruitment:** Upon binding to Reelin, ApoER2 and VLDLR recruit adaptor proteins such as Dab1 (Disabled-1), an intracellular signaling protein, through their cytoplasmic tails.

3. **Dab1 Phosphorylation:** Dab1 is then phosphorylated by Src family kinases (SFKs) and other tyrosine kinases, such as Fyn and Csk, leading to its activation.

4. **Downstream Signaling Cascades:** Activated Dab1 triggers a cascade of downstream signaling events, including:
* **Activation of PI3K/Akt Pathway:** Dab1 recruits and activates phosphatidylinositol 3-kinase (PI3K), which in turn phosphorylates and activates Akt, a serine/threonine kinase. Akt promotes cell survival and growth.
* **Regulation of Rho GTPases:** Dab1 also influences the activity of Rho GTPases, such as Rac1 and RhoA, which control cytoskeletal dynamics and cell morphology.
* **Activation of MAPK Pathway:** Dab1 can activate the mitogen-activated protein kinase (MAPK) pathway, which regulates cell proliferation and differentiation.

5. **Cellular Responses:** The activation of these downstream signaling pathways results in diverse cellular responses, including:
* **Neuronal Migration and Positioning:** Reelin signaling is essential for the proper migration and positioning of neurons during brain development. It regulates radial migration of cortical neurons, cerebellar granule cells, and other neuronal populations.
* **Dendritic Development:** Reelin influences dendritic branching, spine formation, and synapse formation.
* **Synaptic Plasticity:** Reelin signaling plays a role in modulating synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD).

6. **Disruption of Reelin Signaling:** Disruptions in Reelin signaling are associated with neurodevelopmental disorders such as lissencephaly, a severe malformation of the cerebral cortex, and schizophrenia.

Overall, Reelin-mediated signaling is a critical pathway involved in various aspects of brain development and function. It plays a crucial role in neuronal migration, positioning, dendritic development, and synaptic plasticity. Understanding the molecular mechanisms underlying Reelin signaling is essential for elucidating the pathogenesis of neurodevelopmental disorders and for developing potential therapeutic strategies.'
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Proteins (1)

Compounds (3)