In the process of building a brain, countless cells must divide, move, and specialize in a highly coordinated manner. A primary process governing this complexity is interkinetic nuclear migration (INM). This occurs in developing tissues composed of tightly packed, elongated cells known as pseudostratified epithelia. Within the neural tube that gives rise to the brain and spinal cord, the nucleus of each progenitor cell undertakes a rhythmic journey up and down the length of the cell, tied to its cycle of growth and division.
This movement allows a developing tissue to maintain its structure while rapidly increasing the number of cells. The process is a hallmark of neurogenesis, the creation of new neurons, and is central to the proper formation of the vertebrate brain. Understanding this process provides insight into how a complex organ is constructed from a simple sheet of cells, ensuring that cells divide successfully in a crowded environment.
The Journey of the Nucleus During Cell Division
The migration of the nucleus within a progenitor cell is tightly synchronized with the cell’s division cycle. This journey occurs within the tall, slender confines of the cell, which stretches between two boundaries: the apical surface and the basal surface. Following cell division, or mitosis, which always occurs at the apical surface, the nuclei of the newly formed daughter cells begin their migration. During the first phase of growth, known as G1, the nuclei travel away from the apical surface toward the basal side.
Once positioned at the basal end, the nucleus enters the S phase, where the cell’s DNA is duplicated in preparation for the next division. This location provides the necessary space for DNA replication to occur without being constrained by the densely packed cells at the apical surface. Following the S phase, the cell enters the G2 phase, and the nucleus begins its return journey. It migrates back up toward the apical surface, ready for the next round of mitosis. This rhythmic oscillation is a defining feature of progenitor cells in the ventricular zone.
Cellular Motors and Tracks: The Mechanics of INM
The movement of the nucleus during interkinetic nuclear migration is driven by a sophisticated network of internal structures. This machinery relies on the cell’s cytoskeleton, which acts as both a scaffold and a highway system. Microtubules form the primary “tracks” along which the nucleus travels up and down the elongated cell body. These tracks are organized by the centrosome, an organelle that is often physically connected to the nucleus and helps to coordinate its movement.
To move along these microtubule tracks, the cell employs molecular “motor” proteins that convert chemical energy into mechanical force. The apical migration of the nucleus during the G2 phase is powered by a motor protein called dynein. Dynein pulls the nucleus and its associated centrosome toward the apical surface, where mitosis will occur.
The journey back toward the basal surface during the G1 phase involves different mechanisms. While motor proteins like kinesins are involved, some research suggests that the basal movement is also partly a passive process. The upward migration of numerous nuclei in the G2 phase may create a downward pressure, displacing G1 nuclei toward the basal side. A meshwork of actin filaments also helps to position and anchor the nucleus.
Critical Roles in Building Tissues
Interkinetic nuclear migration is a process with profound implications for constructing organized, functional tissues. One of its most direct roles is in managing space within the crowded neuroepithelium. By moving nuclei to the basal side for the S phase, the tissue ensures that DNA replication doesn’t cause a logjam at the apical surface, where mitosis occurs. This spatial and temporal segregation allows for the efficient proliferation of progenitor cells, enabling the massive expansion required to build a brain.
The position of the nucleus along the apical-basal axis can also influence a cell’s fate. As daughter cells are produced at the apical surface, their subsequent nuclear migration can expose them to different signaling molecules and microenvironments at various depths. This differential exposure may help determine whether a cell remains a progenitor and divides again or differentiates into a specialized cell type, such as a neuron.
This regulated movement is important to the formation of complex, layered structures like the cerebral cortex and the retina. In the developing cortex, the layering of different types of neurons is the basis of its computational power. INM ensures that progenitor cells divide correctly to generate the right number and types of neurons, which then migrate to their final positions.
Consequences of Disrupted Nuclear Migration
When the machinery of interkinetic nuclear migration fails, the consequences for brain development can be serious. Errors in this process can disrupt the organized structure of the neural tube, leading to major malformations. If nuclei fail to migrate properly, it can cause overcrowding at the ventricular surface, premature differentiation of progenitor cells, or cell death. These cellular-level problems translate into large-scale anatomical defects in the developing brain.
Specific human neurodevelopmental disorders have been linked to mutations in genes that control INM. For example, lissencephaly, a condition characterized by a “smooth brain” lacking its normal folds, is associated with mutations in genes like LIS1. The LIS1 protein is a known regulator of dynein, the motor protein responsible for pulling the nucleus to the apical surface. A failure in this apical migration disrupts the proper division of progenitor cells and subsequent neuronal placement.
Defects in INM are also implicated in microcephaly, a condition where the brain is abnormally small. If progenitor cells are not positioned correctly for division or are pushed to differentiate too early due to faulty nuclear migration, the overall production of neurons is reduced. The study of INM has provided a window into the underlying causes of these conditions, revealing how a fundamental cellular process is linked to human health.