Our Research

Cerebellum Development

Goal: Identify the molecular and cellular programs regulating how the final structure of this highly patterned and laminated brain structure is generated

The cerebellum represents just 10% of the human CNS volume, yet contains 80% of all neurons. It is highly connected to almost all major brain circuits, with important regulatory roles in both motor and cognitive function. Long studied in mice, we have recently demonstrated that multiple core developmental programs are different in humans, with implications for the pathogenesis of neurodevelopmental disorders involving the cerebellum, including Dandy-Walker malformation, cerebellar hypoplasia, Down Syndrome, autism and medulloblastoma, the most common pediatric malignant brain tumor.

Developing cerebellum stained with an antibody to highlight Purkinje cells and the beautiful lamination and foliation of this structure

(image credit – Parthiv Haldipur)

Stem Cell Differentiation

Goal: Uncover the cellular and molecular networks that control stem cell differentiation in the developing cerebellum.

All cerebellar neurons are generated from 2 primary stem cell zones: the cerebellar ventricular zone gives rise to all GABAergic neurons (including Purkinje cells) and the rhombic lip gives rise to all glutamatergic neurons (including granule neurons and unipolar brush cells). Each zone in humans is expanded spatially and temporally vs mice. Using extensive transcriptomic and epigenomic analyses, we are studying the molecular drivers of stem cell species differences and their differentiation programs.

A single nucleus atlas of the developing cerebellum

(image credit Kim Aldinger – Nat Neurosci. 2021 Aug;24(8):1163-1175)

Modelling Human Disease

Goal: Develop new experimentally tractable models of human disease to define disease mechanisms and discover new therapeutic opportunities.

Using mouse models and in vitro cultures, we are studying the roles of several neurodevelopmental disease genes to define mechanisms of disease pathogenesis which in turn will lead to discovery of new therapeutics.

Adult mouse and human brains demonstrating striking size and complexity differences

(image credit Kathleen Millen)

Brain Health Across The Lifespan

Goal: Define mechanisms of healthy brain aging and homeostasis in Acomys cahirinus (Spiny mice), a mammal with extensive adult regeneration capacity.

Many of the major biological discoveries of the 20th century were made using very few model species. They were chosen for historical experimental tractability, rather than biological attributes relevant to critical biological questions or relevance to pressing global health issues. CRISPR and other technologies now enable us to expand our model organism toolkit to include non-traditional models, including Acomys (Spiny mice). The only known mammal with extensive adult regenerative abilities. Unraveling the mechanisms that drive the naturally selected regenerative capacity in Acomys holds great promise for advancing the development of new pro-regenerative therapeutics in the field of human regenerative medicine