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While studying pyramidal neurons differentiation and cortical development, I fortuitously showed 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. This sparked my interest in brain development and disease and led to a clinical trial that resulted in therapy currently used to treat patients with Niemann-Pick Disease Type C.

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.

We have used this method to reveal that Wnt1-expressing progenitors are progressively restricted during midbrain development and that the Wnt1 lineage contributes to midbrain dopamine neurons in two distinct temporal peaks. In contrast, we show that the Wnt1 lineage originating in the cerebellum primordium at later stages contribute to the diverse array of cerebellum neurons. We have also elucidated the temporal contribution of Gbx2-expressing progenitors contribute to distinct cohorts of neurons in the developing and adult cerebellum, thalamus, and spinal cord.

We use GIFM and the conditional deletion of a novel conditional Wnt1 allele we generated to uncover the dynamic temporal role of Wnt1 in midbrain dopamine neuron development. We are exploiting our knowledge of dopamine neuron development to instruct mouse embryonic stem cells to acquire a specific neuronal fate.

We also combine GIFM with conditional gene deletion to study the role of Tsc1/mTOR in thalamic neuron development and in establishing functional thalamocortical circuits. This approach has identified a novel subcortical node underlying neural and behavioral abnormalities associated with a complex developmental genetic disease, Tuberous Sclerosis.

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Genetic Inducible Fate Mapping demonstrates novel lineage boundary in vivo

Genetic Inducible Fate Mapping showing Wnt1-derived cells during embryogenesis

Wnt1 expression in mouse embryo (E8.5)

midbrain dopaminergic neurons and their axonal projections

Genetic Inducible Fate Mapping: The Wnt1 lineage (red) marked at E10.5 contributes to dopaminergic neurons (green) in vivo

midbrain dopaminergic neuron circuitry schematic

Purkinje and granule neurons of the cerebellum

Genetic Inducible Fate Mapping (GIFM): Wnt1-CreER;R26R mouse embryo brain

MRI of adult Wnt1 sw/sw (Swaying) mouse acquired at the Brown University MRI Research Facility (in collaboration with Ed Walsh & Mike Worden)

MRI of adult Wnt1 sw/sw (Swaying) Brain acquired at the Brown University MRI Research Facility imaged at 3T using the Siemens AC88 gradient insert. Voxel size is 160 µm^3 (in collaboration with Ed Walsh & Mike Worden)

Genetic Inducible Fate Mapping Strategy

Wnt1-derived midbrain dopamine neuron (green/red overlap) in a field of unmarked tyrosine hydroxylase expressing dopamine neurons (red)

One of the lab interests: midbrain dopamine neurons

3D rendering of entire midbrain dopamine neuron population in adult mouse (top). Distribution of dopamine neurons expressing calbindin (green), calretinin (blue), GIRK2 (red).

En1-Cre;Z/EG adult mouse brain (dorsal view). The cerebellum is derived from cells with a history of expressing En1 (green). The inset shows a mid-sagittal view of the cerebellum.

Comparison of reporter alleles in E12.5 embryos (En1:Cre mediated recombination)

Wnt1 derived trigeminal ganglia (Wnt1-CreER;Z/EG with tamoxifen administered at E8.5)

Zervas Lab 2009

Wnt1-derived calbindin-expressing dopamine neurons

mouse ES cell derived dopamine neurons

mouse ES cell derived calbindin-expressing dopamine neurons