Understanding the role of autism genes in cortical development

Cortical malformations arising from abnormal neuronal positioning in the neocortex (neuronal heterotopias) are causative for intellectual disability and intractable childhood epilepsies.  Intriguingly, similar disruptions to the architecture of the neocortex are also observed in autistic children. Mutations in genes that regulate neural stem cell activity and neuronal migration have been implicated in both inherited cortical malformations and autism. This predicts that there is a common molecular mechanism contributing to both neuronal heterotopias and autism spectrum disorders. Our goal is to identify the pivotal molecular pathways that maintain neural stem cell function and neuronal migration in the developing brain and to uncover how mutations in genes implicated in autism impact cortical development.

We have identified the stem cell receptor, Neogenin, as an important regulator of neural stem cell activity and the migration of newborn neurons. We have shown that Neogenin controls the activity of genes known to be prominent risk factors for autism, intellectual disability and schizophrenia. Using mutant mouse and human induced pluripotent stem cell models, we are now exploring the role of this signaling pathway in the development of the neocortex. We are also investigating how mutations in these genes lead to the emergence of autism-like behaviors in our mouse models.

Understanding the molecular mechanisms responsible for hydrocephalus

Project 1
Foetal hydrocephalus is a prevalent neurodevelopmental condition (1 in 3000 births) associated with severe intellectual impairment and motor dysfunction. Ependymal cells (ECs) form a multi-ciliated epithelium at the ventricular surface and the inability to form a cohesive ependymal epithelium has emerged as a major cause of hydrocephalus. ECs are produced from a subpopulation of neural stem cells within the embryonic brain. The failure of these stem cells to produce mature ECs leads to hydrocephalus. Despite the fundamental importance of the stem cell to EC transition, our understanding of the molecular mechanisms governing this process is very limited.

Mutations in Neogenin lead to severe hydrocephalus in mice due to a failure in the production and maturation of ECs. Therefore the Neogenin signaling pathway is critical for the transition from stem cell to mature EC. The aim of our current research is to understand how silencing this pathway contributes to hydrocephalus and to provide proof-of-principle that enhancing Neogenin activity can prevent hydrocephalus.

Project 2 
The choroid plexus is the predominant supplier of cerebral spinal fluid, and abnormal choroid plexus function leads to excessive cerebral spinal fluid production and hydrocephalus. Therefore its importance in maintaining normal brain function is paramount. In this project we investigate the role of the Wnt signaling pathway in choroid plexus formation using loss-of-function and mutagenesis approaches in the developing mouse.

Understanding the molecular processes building complex neural circuits

The contribution of a given neuron to the information flow within the neural circuitry of the brain is governed by the unique three-dimensional architecture of the dendritic tree and the ability to form functional synapses. Abnormal dendritic growth and synapse formation lead to diminished synaptic connectivity and impaired cognitive function associated with neurodevelopmental conditions, including autism and schizophrenia, as well as neurodegenerative disorders such as Alzheimer’s disease. In this project we investigate the role of the Wnt and Neogenin signaling pathways in sculpting dendritic structure and the establishment of synaptic structures.