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J. Cell Biol.,
Volume 144, Number 6, March 22, 1999 1349-1360
* Department of Anatomy and Neurobiology, Washington University Medical School, St. Louis, Missouri 63110; Acetylcholinesterase (AChE) occurs in both
asymmetric forms, covalently associated with a collagenous subunit called Q (ColQ), and globular forms that
may be either soluble or membrane associated. At the
skeletal neuromuscular junction, asymmetric AChE
is anchored to the basal lamina of the synaptic cleft,
where it hydrolyzes acetylcholine to terminate synaptic
transmission. AChE has also been hypothesized to play
developmental roles in the nervous system, and ColQ is
also expressed in some AChE-poor tissues. To seek roles of ColQ and AChE at synapses and elsewhere, we
generated ColQ-deficient mutant mice. ColQ Laboratoire de
Neurobiologie Cellulaire et Moléculaire, Ecole Normale Superieure, 75005 Paris, France; and § Laboratoire de Neurobiologie
Cellulaire et Moléculaire, UPR9040, CNRS, 91198 Gif-sur-Yvette, France
/ mice
completely lacked asymmetric AChE in skeletal and
cardiac muscles and brain; they also lacked asymmetric
forms of the AChE homologue, butyrylcholinesterase.
Thus, products of the ColQ gene are required for assembly of all detectable asymmetric AChE and butyrylcholinesterase. Surprisingly, globular AChE tetramers
were also absent from neonatal ColQ/ muscles, suggesting a role for the ColQ gene in assembly or stabilization of AChE forms that do not themselves contain
a collagenous subunit. Histochemical, immunohistochemical, toxicological, and electrophysiological assays all indicated absence of AChE at ColQ/ neuromuscular junctions. Nonetheless, neuromuscular
function was initially robust, demonstrating that AChE
and ColQ do not play obligatory roles in early phases of
synaptogenesis. Moreover, because acute inhibition of
synaptic AChE is fatal to normal animals, there must
be compensatory mechanisms in the mutant that allow the synapse to function in the chronic absence of
AChE. One structural mechanism appears to be a partial ensheathment of nerve terminals by Schwann cells.
Compensation was incomplete, however, as animals lacking ColQ and synaptic AChE failed to thrive and
most died before they reached maturity.
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