In one key project we showed that miRNA malfunction is causatively-related to Amyotrophic Lateral Sclerosis (ALS), a devastating neurodegenerative disease. Since genes encoding for RNA-binding proteins are often mutated in ALS, we now study how these RNA-binding proteins interact with the core miRNA machinery. We also explore the consequent disruption of neuronal pathways, downstream of specific miRNAs. These studies support a new view of ALS as a miRNA pathology.

Regulation of gene expression by endogenous small RNAs, called microRNAs (miRNA), affects many cellular processes in health and disease.

While hundreds of miRNA genes were discovered in recent years, the principles underlying the coordination of posttranscriptional regulation by miRNAs with signaling cascades and transcriptional networks are not well understood.

Additionally, characterizing the impact of specific miRNA genes on developmental and disease processes should provide important insight into human pathologies.
Research in the Hornstein group is aimed at uncovering the principles of miRNA function and the role of microRNAs in development and disease by utilizing mouse models, molecular and bioinformatic approaches.

miRNA activity appears to be essential for the proper function of insulin-secreting beta cells within the pancreas. For example, we discovered that in vivo perturbation of miRNA activity leads to Diabetes Mellitus. As a result of our analysis, we uncovered a miRNA-based mechanism for insulin synthesis. We now study the response of specific miRNAs to the metabolic state upstream of insulin production.

Notably, miRNAs are important also in pancreatic development. Our work explains the principles of miRNA-based commitment to a specific fate in differentiation. We have shown how specific miRNA genes control the stem cell pool, regulate developmental transitions and promote acquisition of a robust developmental outcome in the chondrocyte, monocyte and pancreatic lineages.

In summary, miRNA genes are pivotal in development and in mature functional cells. Our discoveries shed light on miRNA networks, highly relevant to major human pathologies.