Genetic analysis of collagen Q: Roles in acetylcholinesterase and butyrylcholinesterase assembly and in synaptic structure and function

Acetylcholinesterase (AChE) occurs in both asymmetric forms, covalently ass ociated with a collagenous subunit called Q (ColQ), and globular forms that may be either soluble or membrane associated. At the skeletal neuromuscula r junction, asymmetric AChE is anchored to the basal lamina of the synaptic cleft, where it hydrolyzes acetylcholine to terminate synaptic transmissio n. AChE has also been hypothesized to play developmental roles in the nervo us system, and ColQ is also expressed in some AChE-poor tissues. To seek ro les of ColQ and AChE at synapses and elsewhere, we generated ColQ-deficient mutant mice. ColQ(-/-) mice completely lacked asymmetric AChE in skeletal and cardiac muscles and brain; they also lacked asymmetric forms of the ACh E homologue, butyrylcholinesterase. Thus, products of the Cola gene are req uired for assembly of all detectable asymmetric AChE and butyrylcholinester ase, Surprisingly, globular AChE tetramers were also absent from neonatal C olQ(-/-) muscles, suggesting a role for the Cola gene in assembly or stabil ization of AChE forms that do not themselves contain a collagenous subunit. Histochemical, immunohistochemical, toxicological, and electrophysiologica l assays all indicated absence of AChE at ColQ(-/-) neuromuscular junctions . Nonetheless, neuromuscular function was initially robust, demonstrating t hat AChE and ColQ do not play obligatory roles in early phases of synaptoge nesis. Moreover, because acute inhibition of synaptic AChE is fatal to norm al animals, there must be compensatory mechanisms in the mutant that allow the synapse to function in the chronic absence of AChE, One structural mech anism appears to be a partial ensheathment of nerve terminals by Schwann ce lls. Compensation was incomplete, however, as animals lacking ColQ and syna ptic AChE failed to thrive and most died before they reached maturity.