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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 led to an ongoing clinical trial and sparked my interest in brain development and disease.

I am using Genetic Inducible Fate Mapping to forge a link between gene expression during embryogenesis and the behavior of cells during brain development. This method revealed that the Wnt1 lineage contributes to midbrain dopaminergic neurons. I then showed that Wnt1 is required for subpopulations of dopaminergic neurons that mediate movement and cognition; I am now evaluating the pathological and behavioral correlates in these mice, which may be relevant to Parkinson's disease and schizophrenia.

I am using state-of-the-art genetic approaches to investigate dopaminergic neuron development, the relationship between genetic lineage and dopamine neuron circuitry and how perturbations in these events may contribute to neurological diseases.

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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.

Partial 3D rendering of calbindin-expressing dopamine neuron

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