Spatially patterned organoids: regionalization, cell fate and lamination in cortical development and neuronal migration disorders

Objective

The development of the mammalian cerebral cortex depends on the precise control of cell proliferation, migration, and neuronal diversity along both radial and tangential dimensions which ensure cortical regionalization and lamination and ultimately the formation of functional areas. These processes depend on the formation of focal organizing centers within the early neural plate. These centers secrete morphogens in gradients to pattern the developing cortex at short range and locally produce the first-born neurons, the Cajal-Retzius cells (CRs). These cells migrate at the surface of the cerebral cortex, establishing long-range patterning through morphogen production and lamination via Reelin secretion. Yet, major gaps in our understanding of these processes, particularly regarding human-specific mechanisms, limit insights into normal and pathological development. Brain organoids are the only experimental models of human brain development. However, they fail to reproduce cortical regionalization and lamination, likely due to the absence of focal organizing centers and a lack of CR-like cells at their surface. This proposal aims to generate patterned and layered cortical organoids by investigating the mechanisms behind cortical organizing center formation, CR subtype induction, and migration in both mouse and human models. With this next generation of cortical organoids, we will explore region-specific cortical development (including progenitor divisions, cell fate, and architecture), evolutionary adaptations, and pathological conditions. This will be achieved through a synergistic collaboration of four partners with complementary expertise in cortical development and CRs biology (P1), morphogen control of tissue morphogenesis and cell fate in organoids (P2), biophysics and microfluidics (P3) and cell fate decisions in cerebral organoids (P4).