Cajal-Retzius cells at the heart of brain development during embryogenesis

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The development of the cerebral cortex, the superficial layer of the brain, depends on multiple coordinated steps, including the correct migration of neurons. A very early cell type, Cajal-Retzius (CR) cells, play a central role in this process, notably through the production of a protein called Reelin (Reln). This protein is essential for the layered organization of the cortex and the structuring of the hippocampus, a key area for memory and learning. While most CRs disappear after birth, their transient presence is crucial : a study conducted at Institut Imagine has shown that their early elimination disrupts neuronal migration and the proper development of brain structures. In particular, the researchers observed that a lack of Reln prevents the normal migration of neurons in the cortex, and that CRs also influence the formation of brain folds, independently of this protein. These folds, which increase cortical surface area, are altered in certain rare genetic diseases, such as pachygyria (cortex too smooth) or polymicrogyria (cortex abnormally folded). This work opens up new avenues for understanding the origins of these malformations, and refines our knowledge of the role of Reln and CR in brain development.

The development of the mammalian cerebral cortex relies on the precise coordination of progenitor patterning and proliferation, specification of cellular identities and neuronal migration, which ultimately lead to the establishment of mature functional circuits. Cajal-Retzius (CR) cells play a key role in these processes. CRs are among the earliest neurons in the cerebral cortex, the outer layer of the brain that gives it its furrowed appearance.

Shortly after birth, CRs undergo a programmed death (known as apoptosis) and almost completely disappear, although it is estimated that around 15% survive into adulthood in the hippocampus, the brain structure that plays a central role in cognition, memory, learning and spatial location. Precise control of the presence and disappearance of CRs has been shown to be essential for the establishment of cortical and hippocampal circuits.

There are many different types of CR ; however, they all share common characteristics, notably the expression of the secreted protein Reelin (Reln). Reln is a glycoprotein strictly necessary for the establishment of the layered pattern of the cerebral cortex, and the organization of the hippocampus. However, the precise function of Reln remains elusive: it has been proposed both to promote neuronal migration and to act as a stop signal.

The specific contribution of CRs and the Reln protein to corticogenesis has been studied by observing genetic models deficient in one or more types of CR, leading to an incomplete understanding of the consequences of CR loss at the embryonic stage and highlighting the need for further molecular characterization. Fréderic Causeret's team in the “Genetics and development of the cerebral cortex” laboratory, led by Alessandra Pierani at Institut Imagine (Inserm, AP-HP, Université Paris Cité), has recently highlighted the molecular mechanisms involved in specifying the fate of a certain type of CR.

In collaboration with Nathalie Spassky's team at IBENS (Institut de Biologie de l'ENS), they triggered their massive death during embryonic development, to assess the impact of such a massive loss of CRs, after a short period of regular presence, on cortical and hippocampal development. They discovered that, in the event of deficiency of Reln synthesized by CRs in the middle of corticogenesis, radial migration in the cortex is arrested. CRs also have an impact on hippocampal fissure formation and cortical folding, but independently of Reln.

A century after their initial description by Santiago Ramón y Cajal and Gustaf Retzius, CRs have remained an understudied cell type. These results underline the importance of CR-derived Reln in ensuring the correct termination of neuronal migration during brain development. Further work will be required to assess the extent to which molecular players contribute to Reln-independent functions for CRs.

In addition, both CRs and Reln appear to be potential players in cortex folding. To increase its surface area, the cortex is folded by furrows of varying depth, delimiting ridges called gyri. However, there are genetic diseases that affect the proper course of gyration, i.e. the formation of cerebral convolutions during embryogenesis, and of different types : gyration deficit leading to an insufficiently folded cortex (pachygyria), or conversely excessive gyration leading to small and numerous or large but few furrows (polymicrogyria).

This work, the results of which were recently published in the scientific journal Development, provides valuable insights into the pathogenesis of developmental disorders of the cerebral cortex linked to the presence or absence of CR and Reln. They also enrich our understanding of the precise role of the Reln protein, several mutations of which have already been identified in patients affected by cortical malformations.

Reference :
Differential contribution of P73+ Cajal-Retzius cells and Reelin to cortical morphogenesis
V Elorriaga et al, Development, 2025
Corresponding author : Frédéric Causeret
doi:10.1242/dev.204451