Cohorts of neurons are organized into anatomically specialized regions that are functionally connected by neural circuits. Allocating distinct types of neurons from uncommitted progenitor cells and the precision of neuronal connectivity requires the coordination of cell fate programming, differentiation, and neural circuit formation. I am interested in how genes and signaling pathways function at specific developmental stages to control these processes. My lab studies these mechanisms in the thalamus, striatum, and dopamine system because these regions regulate perception, sensation, sleep, motivation, and movement and are affected in complex brain disorders including autism, epilepsy, and schizophrenia. Using genetic approaches in mice, we ascertain how neuronal subtypes are established and become functionally connected. We also determine how mutations induced at specific embryonic stages affect brain development and cause complex behavioral phenotypes. Our knowledge of developmental mechanisms is being used to advance stem cell and pharmacological therapies to ameliorate brain disease.
Genetic circuit tracing. Thalamocortical axons were marked during embryogenesis and analyzed at adult stage. Modified from Normand et al. 2013.
BIOGRAPHY. While studying pyramidal neurons differentiation and cortical development, I fortuitously found that ectopic dendrite growth in metabolic brain disorders was accompanied by intra-neuronal cholesterol and ganglioside accumulation. I subsequently designed a therapeutic approach that ameliorated neuropathology in animal models of Niemann-Pick Disease Type C (NPC) and led to a therapeutic approach currently used to treat NPC. These findings sparked my interest in brain development and disease, which I still work on today.Â
Currently, my lab uses Genetic Inducible Fate Mapping (GIFM) to spatially and temporally mark small cohorts of cells and their progeny based on the expression of specific genes during embryogenesis. We then track these marked lineages to determine their behavior and contribution to brain regions, specific classes of neurons, and terminal neuronal fate generated during brain development. GIFM revealed that the Wnt1 lineage progressively restricted during development and contributes to midbrain dopamine (MbDA) neurons in two distinct temporal peaks. In contrast, the Wnt1 lineage originating in the cerebellum primordium at later stages contributes to a diverse array of cerebellum neurons. GIFM also elucidated the temporal contribution of Gbx2-expressing progenitors to distinct cohorts of neurons in the cerebellum, thalamus, and spinal cord.
We couple GIFM and the conditional deletion to uncover spatial and temporal roles of genes and signaling pathways during development: We used our novel "floxed" Wnt1 allele to uncover the dynamic temporal function of Wnt1 in MbDA neuron development and are exploiting our knowledge of MbDA neuron development to instruct embryonic stem cells to acquire a specific neuronal fate.
We also combine GIFM with the conditional gene deletion to study the temporal role of Tsc1/mTOR pathway in subcortical neuronal development and in establishing thalamocortical circuits. This approach identified a novel subcortical node underlying neural circuit and behavioral abnormalities associated with the complex developmental genetic disease, Tuberous Sclerosis.