To determine the mechanisms that specify neuronal fate and connectivity, our lab focuses on two interconnected areas of study:
- Investigating cellular and molecular pathways by which cell-surface recognition molecules and somatic mosaicism determine cell identity to ensure proper neural circuit formation during development.
- Identification of the genetic causes and functional characterization of molecular, cellular, and circuit mechanisms that are dysregulated and lead to neurodevelopmental disorders in humans
Our lab takes advantage of a battery of modern multidisciplinary approaches including molecular and cellular biology, next generation sequencing, animal models, and a variety of state-of-the-art imaging techniques. Particularly, we use induced pluripotent stem cells (iPSCs) from patients as well as CRISPR edited iPSC to generate neural progenitors, neurons, and forebrain organoids predisposed to neurodevelopmental disorders.
Ongoing research projects in our lab include:
Uncovering cell-cell recognition processes relevant to the establishment of neural circuits during development and disease.
Developing neurons integrate into functional circuits through a series of cell recognition events, which include neuronal sorting, axon and dendrite patterning, synaptic selection, among others. Our research focuses on cell-surface recognition molecules, particularly protocadherins (PCDHs), that mediate interactions between neurons to discriminate and select appropriate targets in the developing brain. We have made significant advances to understand PCDH function during development and disease by studying PCDH12 and PCDH19, two PCDHs that cause NDDs. Using a mouse model of PCDH19 Clustering Epilepsy, we have recently reported that heterozygous female mice exhibit a lower seizure threshold and a more severe seizure phenotype than controls, while hemizygous null males are not affected, mimicking the pattern of inheritance in patients (Rakotomamonjy et al., 2020). Previously, we and others have described that loss of function pathogenic variants in PCDH12 results in a rare NDD, characterized by microcephaly, white matter abnormalities, intellectual disability and epilepsy (Guemez-Gamboa et al., 2018). However, despite the highly deleterious outcome resulting from PCDH12 deficiency, little is known about its role during brain development and disease. We are currently investigating the critical and broad involvement of PCDH12 in cortical development; we aim to reveal the pathogenic mechanisms underlying PCDH12-related NDDs. This work was funded by a NIH NINDS K99/R00 Award.
Identifying pathogenic mechanisms underlying PACS1 Syndrome.
Several large-scale genetic studies have been conducted on NDD patients and their families, leading to hundreds of risk genes being identified. However, our understanding of the mechanisms by which these genes act has lagged, limiting translation of genetic findings into the clinic. PACS1 Syndrome, an NDD characterized by ASD, intellectual disability, craniofacial abnormalities, and epilepsy, is caused by a unique Arginine to Tryptophan (p.R203W) substitution in the PACS1 protein. Even with nearly 200 patients identified with this identical substitution, we are still far from understanding both the disease mechanisms and the endogenous PACS1 function during nervous system development. Therefore, I joined forces with the PACS1 Research Foundation to generate publicly available resources, communicate with families, and boost research (Rylaarsdam et al., 2022). Current efforts in my lab aim to uncover how PACS1 regulates nervous system development and homeostasis and causes neurological disorders when disrupted. In a recent study, we use iPSC-derived neuronal models to assess the impact of the p.R203W variant in cortical development and suggested that therapies developed towards either clearing the variant-containing PACS1 protein or targeting convergent mechanisms of ASD could be beneficial for PACS1 syndrome patients (Rylaarsdam et at., 2022 BioRxiv). Results from our current projects (funded by NIH NINDS R01) in combination with our biomarker discovery efforts (funded by the PACS1 Syndrome Research Foundation) will likely uncover novel therapeutic strategies.
