Reelin is a large extracellular matrix protein that plays critical roles in neuronal migration, cortical layer formation, and synaptic plasticity during brain development and in the adult brain [1][2]. The protein is encoded by the RELN gene on chromosome 7q22.1 and is secreted by Cajal-Retzius cells in the developing cortex, as well as by certain neuronal populations in the adult brain. Reelin signaling through ApoE receptors (Apoer2/VLDLR) modulates dendritic spine morphology, synaptic function, and cognitive processes including learning and memory [3]. Reelin dysfunction has been strongly implicated in Alzheimer's disease (AD) pathogenesis, where reduced Reelin expression contributes to synaptic dysfunction, amyloid pathology, and cognitive decline [4][5].
| Attribute | Value |
|---|---|
| Protein Name | Reelin |
| Gene Symbol | RELN |
| UniProt ID | P78536 |
| Molecular Weight | ~388 kDa (full-length) |
| Subcellular Localization | Extracellular, cell surface |
| Protein Family | Reelin family |
| Chromosome | 7q22.1 |
| Expression | Cortex, hippocampus, cerebellum |
Reelin is one of the largest secreted proteins known, containing 3,460 amino acids with a complex domain organization [1:1][6]:
Signal peptide (residues 1-27): Targets protein for secretion via secretory pathway
N-terminal Reelin domain (residues 28-189):
EGF-like domains (residues 190-327):
Reelin repeat domains (residues 328-3460):
| Domain | Residues | Function |
|---|---|---|
| Signal peptide | 1-27 | Secretory targeting |
| N-terminal domain | 28-189 | Receptor binding, signaling |
| EGF-like region | 190-327 | Protein interactions |
| Reelin repeats R1-R8 | 328-3460 | Core functional domains |
Reelin is proteolytically processed into functional fragments:
These fragments have distinct functions and can activate different signaling pathways.
Reelin's best-characterized function is in cortical lamination [1:2][2:1]:
The mechanism involves:
In the adult brain, Reelin modulates critical synaptic functions [3:1][7]:
Long-term potentiation (LTP):
Long-term depression (LTD):
Dendritic spine morphology:
Synaptic vesicle release:
Reelin continues to function in the adult brain [8]:
Reelin affects neuronal signaling properties [9]:
Reelin is significantly implicated in AD pathogenesis through multiple mechanisms [4:1][5:1][10]:
Reelin interacts with tau pathology in AD [12]:
The ApoE receptors (Apoer2/LRP8 and VLDLR) mediate Reelin effects [13]:
Reelin modulates cytoskeletal dynamics [14]:
Reelin is strongly implicated in schizophrenia [15][16]:
Approaches to restore Reelin function [17][18]:
| Approach | Mechanism | Status |
|---|---|---|
| Recombinant Reelin | Protein replacement | Preclinical |
| Gene therapy | Increase Reelin expression | Research |
| Small molecules | Activate signaling pathway | Discovery |
| Peptide fragments | Functional domains | Research |
| Partner | Interaction | Functional Consequence |
|---|---|---|
| Apoer2/LRP8 | Receptor binding | Signal transduction |
| VLDLR | Receptor binding | Signal transduction |
| Dab1 | Adaptor protein | Intracellular signaling |
| Disabled-1 | Substrate | Cytoskeletal effects |
| APP | Possible interaction | Amyloid processing |
Reelin as a biomarker:
A role for reelin in the development of forebrain circuitry. 1995. ↩︎ ↩︎ ↩︎
Reelin and brain development. 2007. ↩︎ ↩︎
Reelin and synaptic plasticity. 2002. ↩︎ ↩︎
Reelin in Alzheimer's disease. 2006. ↩︎ ↩︎
Reelin in synaptic function. 2017. ↩︎
Reelin in adult neurogenesis. 2008. ↩︎
Reelin and tau pathology in AD. 2021. ↩︎
Reelin and neurodegeneration. 2022. ↩︎