Developmental cholinergic mechanisms: Do not forget the cholinesterases!

Cholinergic mechanisms are most relevant for development, physiology and disease, both in neural and non-neural systems. Whether acetylcholine (ACh) itself, or one of its system components thereby exerts a leading role, often remains open. While most developmental studies have focused on ChAT, which is the most reliable marker for cholinergic systems, and/or on AChRs, cholinesterases (AChE, BChE) were often neglected, although they will determine – due to their fast actions - the efficacy of any cholinergic assembly. We have investigated embryonic “non-classical” functions of ChEs for more than three decades. AChE is a most remarkable protein, since it is fast, appears in many molecular forms and is regulated by elaborate genetic networks. Detected histochemically, AChE is expressed in many tissues during development and in many mature organisms, as well as in healthy and diseased states. Extensive in vivo and in vitro studies from our and other labs strongly support views that AChE can be considered a highly co-opting protein, since it can combine such diverse functions within one molecule. Here we report that besides their major effects during retinal development, non-neural ChEs have i) pronounced effects on cartilage and bone formation in chick and mouse, and that ii) overexpressing AChE in mouse embryonic stem cells decreases cell proliferation. Clearly, when discussing non-neural cholinergic mechanisms, one should never forget ChEs.