Modeling and Targeting LRCH2-Associated Cerebellar Hypoplasia Using Air-Liquid-Interface Human Cerebellar Organoids and Zebrafish Embryos

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

The human cerebellum is a key brain region that helps us move, think, and keep our balance. It holds most of the brain’s neurons and develops over a long period, starting early in the embryo and maturing late in life. This makes it especially vulnerable. One condition that can arise is cerebellar hypoplasia (CHy), in which the cerebellum is smaller and malformed, leading to issues like ataxia, poor coordination, balance, and motor control. Currently, there is no effective treatment. A rare genetic form of CHy has been linked to the gene LRCH2 but we don’t yet understand what this gene does. It may help cells divide and grow properly by controlling the cell’s skeleton and possibly influencing the function of other genes. To study this, we will use a new cutting-edge 3D model of the human cerebellum, called air-liquid interface cerebellar organoid (ALI-CeOs).This model closely mimics real human cerebellar development over many months in the petri-dish and, for the first time, allows detailed study of disease progression during neuron maturation. Furthermore, we will sustain our findings by analysing the function of LRCH2 in the living animal. Using these organoids, along with zebrafish embryos, we will study what happens when LRCH2 is missing or mutated. We’ll look at how it affects the growth of brain cells, the way neurons extend their connections, and how mature neurons form. Then, we’ll search for drugs that can reverse the damage. Our zebrafish model allows rapid testing of hundreds of compounds to find potential treatments. This work will uncover how LRCH2 helps build the cerebellum and identify drugs that could help treat not just this rare condition, but also other types of cerebellar ataxias that share similar brain development problems.