Do RASopathies and ciliopathies share underlying developmental mechanisms?

Abstract Elucidating the key mechanisms underlying rare genetic disorders is particularly challenging, as their phenotypes typically manifest from the earliest stages of development. While ‘rare’ suggests these diseases are marginal problems, collectively millions of individuals are affected, often with diagnostic uncertainties and no therapeutic options. Yet the rarity of individual diseases implies that classical clinical studies are not possible and costly drug development fails to meet a sufficiently large clientele. Therefore, it is critical to develop cost effective predictive disease models that could facilitate the translation of molecular mechanistic insights. Likewise, we need to develop a more comprehensive view on certain disorders that appear phenotypically similar. Here we hypothesize that two major rare disease families, RASopathies and ciliopathies, which have several phenotypic similarities also share a common mechanistic denominator: defective cilia function. Primary cilia are the ‘antennae’ of the stem- and progenitor cells that host critical developmental pathways. Based on our most recent data, we argue that the RAS pathway fundamentally affects ciliogenesis in a differentiating system. Notably KRAS may protect ciliation and thus stemness during asymmetric cell divisions, thus fundamentally shaping cell differentiation hierarchies. As small imbalances in cellular hierarchies accumulate throughout development, we end up with exponentially aggravated defects in multiple organ systems as typically seen in these disorders. We discuss how simple cellular differentiation models in combination with zebrafish disease models may have the potential to drive not only our understanding of the underpinning molecular and cellular process but also enable drug screening. We propose that primary cilia are important to understand several developmental diseases and also tissue homeostasis in the adult.