Reelin is a large protein found outside nerve cells, functioning as a signal for brain development. It is a glycoprotein, a protein with attached sugar chains. The protein gained its name from a specific mouse mutant identified in 1951, known for its distinct, uncoordinated “reeling” gait. This unusual movement was later linked to a deficiency in the protein within these mice.
The Architect of the Developing Brain
Reelin guides the embryonic development of the brain, overseeing the precise organization of its complex structures. It directs the migration of billions of neurons, ensuring each one settles into its exact predetermined position within the developing cerebral cortex. This meticulous process is foundational for establishing the brain’s intricate and highly functional layered architecture, enabling the formation of proper neural circuits.
Reelin is primarily secreted by specialized, transient neurons known as Cajal-Retzius cells, positioned in the outermost layer of the developing cortex, called the marginal zone. These cells establish an extracellular environment abundant with reelin, generating a chemical gradient that influences the radial movement of newly formed neurons. Reelin also plays a role in the proper development of the cerebellum and hippocampus, ensuring their correct cellular arrangements and connections.
The protein orchestrates an “outside-in” layering process, where successive waves of neurons migrate past earlier ones to form the deeper layers of the cortex. This ensures that the most recently generated neurons travel the furthest to occupy the superficial layers. Reelin acts as a precise “stop” signal, instructing these migrating neurons when to detach from their radial glial guides and integrate into their specific cortical layer. This controlled detachment and positioning mechanism ensures the proper formation of the cerebral cortex’s six distinct layers, a complex and highly coordinated process termed cortical lamination. This orderly arrangement is paramount for the brain to process information effectively and develop complex cognitive functions.
The “Reeler” Phenotype and Human Disorders
A complete absence or severe deficiency of reelin leads to profound developmental consequences, first observed in the “reeler” mouse. This mouse exhibits an uncoordinated, “reeling” movement, resulting from severe brain malformations. Their cerebral cortex is jumbled and inverted, with improperly organized layers, and the cerebellum is underdeveloped. These defects arise from the neurons’ failure to migrate and position correctly due to the lack of reelin.
A parallel condition exists in humans. Mutations in the human RELN gene, which encodes reelin, cause a rare but serious brain malformation: Lissencephaly with Cerebellar Hypoplasia. This disorder results in a “smooth brain” lacking normal folds and layers, and a small, abnormal cerebellum. Individuals with this condition experience profound developmental delays, intellectual disability, and recurrent seizures due to widespread brain disorganization.
Reelin’s Function in the Adult Brain
Reelin remains present in the adult brain, though at lower levels than during development and in different regions, primarily secreted by GABAergic interneurons. In adulthood, its role shifts from guiding neuronal migration to fine-tuning neuronal connections. Reelin modulates synaptic plasticity, the ability of synapses to strengthen or weaken over time. This process forms the basis for learning and memory.
The protein helps maintain synaptic structure and function. It influences the density of dendritic spines, small protrusions on neurons that receive inputs, and affects the function of certain receptor types, like NMDA receptors. By regulating these synaptic properties, reelin ensures efficient communication between brain cells, necessary for complex cognitive processes. Disruptions to reelin signaling in adults can impair spatial learning and long-term potentiation, a measure of synaptic strengthening.
Connection to Complex Neurological Conditions
Dysregulation of reelin levels or signaling is implicated in several common and complex neurological conditions. This differs from severe malformations caused by a near-total absence of reelin, involving more subtle alterations. Altered reelin expression or activity may contribute to conditions such as schizophrenia, bipolar disorder, and autism spectrum disorder. For instance, lower reelin levels have been observed in certain brain regions of individuals with schizophrenia and bipolar disorder.
Reelin is considered a contributing or risk factor in these conditions, rather than their sole cause, reflecting their complex nature. In Alzheimer’s disease, for example, reelin may interact with amyloid-beta plaques, hallmarks of the disease. Some studies suggest reduced reelin signaling could accelerate plaque formation, while others indicate a more complex relationship. These findings highlight reelin’s broader implications in neuropsychiatry, where its proper regulation appears important for maintaining brain health and function.