The Reelin protein is an extracellular signaling molecule with a well-understood role in brain development. It is a large glycoprotein—a protein with an attached carbohydrate—secreted by cells to influence the surrounding environment. This protein guides the intricate process of neuronal migration, ensuring nerve cells settle in their correct locations. Beyond its foundational role in development, Reelin also contributes to processes like learning and memory in the mature brain.
The Reelin Signaling System
Reelin transmits its influence through a signaling pathway that begins when the protein is released into the extracellular space. During brain development, it is primarily secreted by neurons known as Cajal-Retzius cells, found in the developing cerebral cortex and hippocampus. The protein then acts as a messenger, initiating a cascade of events upon reaching its target neurons.
The signal is received by receptors on the surface of target nerve cells. The two main receptors for Reelin are the Apolipoprotein E receptor 2 (ApoER2) and the Very Low-Density Lipoprotein Receptor (VLDLR). When Reelin binds to these receptors, it triggers a change within the receiving neuron, much like a key turning in a lock. This binding event is the first step in communicating the external Reelin signal to the internal machinery of the cell.
Once Reelin binds to its receptors, the signal is carried inside the cell by an adapter protein called Disabled-1 (Dab1). This binding causes Dab1 to become phosphorylated, a chemical modification where a phosphate group is added to the protein. The phosphorylation of Dab1 activates a series of downstream chemical reactions. These pathways direct changes in the neuron’s internal scaffolding, or cytoskeleton, guiding its movement and placement.
Reelin’s Role in Building the Brain
Reelin’s primary function during brain development is managing neuronal migration. This process is important for forming brain structures with a layered organization, such as the cerebral cortex, hippocampus, and cerebellum. Reelin acts as a stop signal, telling migrating neurons they have reached their final destination and ensuring they settle in the correct layer.
In the cerebral cortex, responsible for higher cognitive functions, Reelin establishes its distinct six-layered structure. The cortex develops in an “inside-out” pattern, where new neurons travel past older ones to find their place in the outermost layers. Reelin, secreted from the top layer of the cortex, orchestrates this layering, ensuring each new wave of neurons forms the next successive layer.
The significance of this protein is illustrated by the “reeler” mouse, a naturally occurring mutant strain that lacks functional Reelin. These mice exhibit severe motor problems, including a characteristic reeling gait and tremors, due to a profoundly disorganized brain structure. In reeler mice, the layered structures of the brain fail to form correctly, with neurons positioned in a jumbled, almost inverted, manner. This phenotype provided compelling evidence for Reelin’s role in guiding brain architecture.
Reelin’s Functions Beyond Brain Development
Reelin continues to function in the adult brain after its structure is established. A primary role is modulating synaptic plasticity, which is the ability of synapses—the connections between neurons—to strengthen or weaken over time. This process is a mechanism for learning and memory formation.
Reelin influences synaptic plasticity by participating in processes like Long-Term Potentiation (LTP), which strengthens synaptic connections, and Long-Term Depression (LTD), which weakens them. By modulating these phenomena, Reelin helps refine neural circuits in response to new experiences or information.
There is also evidence to suggest that Reelin may have neuroprotective properties in the adult brain. It is also involved in regulating the release of neurotransmitters, the chemical messengers that neurons use to communicate with each other. Furthermore, Reelin guides the migration of new neurons generated in specific regions of the adult brain, a process known as adult neurogenesis.
When Reelin Goes Awry: Links to Neurological Disorders
Disruptions in the Reelin signaling pathway are associated with several neurological and psychiatric conditions. For example, altered Reelin levels or function are observed in individuals with schizophrenia, which may contribute to the disorder’s symptoms. The precise connection is still under investigation but is thought to involve both developmental and adult functions of the protein.
The Reelin pathway has also been implicated in Autism Spectrum Disorder (ASD). Studies have found mutations in the Reelin gene in some individuals with ASD. This suggests that disruptions in neuronal migration or synaptic function from faulty Reelin signaling could play a part in the condition.
Links have also been established between Reelin and neurodegenerative diseases like Alzheimer’s disease. Research suggests that Reelin may interact with the pathways that lead to the accumulation of amyloid-beta plaques, one of the hallmarks of Alzheimer’s.
Severe disruptions in the Reelin pathway can lead to a condition called lissencephaly, or “smooth brain,” where the normal folds of the cerebral cortex do not form. Additionally, some forms of epilepsy have been linked to variants in the Reelin gene.