Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1−/− cerebellar phenotype. SDF1α also rescues the Foxc1−/− phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.
The part of the brain responsible for coordinating and fine-tuning movement, sensory processing and some cognitive functions—the cerebellum—is found tucked away at the back of the brain, where it sits in a hollow in the skull called the posterior fossa. In a relatively common neurological disorder called Dandy-Walker malformation, part of the cerebellum doesn't develop and the posterior fossa is abnormally large.
One contributing factor to Dandy-Walker malformation is the loss of a protein called Foxc1. This protein is a so-called transcription factor, meaning it activates other genes, and so it has various important roles in helping an embryo to develop. In mouse embryos, the gene that produces Foxc1 is not activated in the developing cerebellum itself, but rather in the adjacent mesenchyme, a primitive embryonic tissue that will develop into the membranes that cover the brain and the skull bones that define the posterior fossa. This led Haldipur et al. to propose that the mesenchyme and the cerebellum communicate with each other as they develop.
To investigate this idea, Haldipur et al. carefully analysed how the development of the mouse cerebellum goes awry when Foxc1 is absent. This revealed that Foxc1-deficient mice have lower numbers of a type of cell called radial glial cells in their cerebellum. These are ‘progenitor’ cells that develop into the various types of cell found in the cerebellum, and also act as a scaffold for other neurons to migrate across. Therefore, the loss of radial glial cells in Foxc1-deficient mice substantially disrupts how the cerebellum develops, and how the neurons in the cerebellum work.
One gene activated by the Foxc1 protein encodes another protein called SDF1-alpha. This protein is released from the tissue that will develop into the posterior fossa, and binds to a receptor protein that is present on radial glial cells in the cerebellum. When this binding occurs, the radial glial cells grow and divide, and so the embryo's cerebellum also grows. Haldipur et al. found that mouse embryos specifically missing this receptor develop many of the abnormalities seen in Foxc1-deficient mice and further, when SDF1-alpha was provided back into Foxc1-deficient cerebella, the defects were rescued. This suggests that the cerebellar defects caused by the loss of Foxc1 stem from disrupting the signalling pathways that are triggered by the interaction between SDF1-alpha and its receptor.
These studies highlight that the brain does not develop in isolation. It is strongly dependent on the signals it receives from the embryonic mesenchyme that surrounds it. Identifying these signals and understanding how they can be disrupted by both genetic and non-genetic causes, such as inflammation, may be key to understanding this important class of brain birth defects.