ACETYLCHOLINESTERASE-TRANSGENIC MICE DISPLAY EMBRYONIC MODULATIONS INSPINAL-CORD CHOLINE-ACETYLTRANSFERASE AND NEUREXIN I-BETA GENE-EXPRESSION FOLLOWED BY LATE-ONSET NEUROMOTOR DETERIORATION

To explore the possibility that overproduction of neuronal acetylcholi nesterase (AChE) confers changes in both cholinergic and morphogenic i ntercellular interactions, we studied developmental responses to neuro nal AChE overexpression in motoneurons and neuromuscular junctions of AChE-transgenic mice. Perikarya of spinal cord motoneurons were consis tently enlarged from embryonic through adult stages in AChE-transgenic mice. Atypical motoneuron development was accompanied by premature en hancement in the embryonic spinal cord expression of choline acetyltra nsferase mRNA, encoding the acetylcholine-synthesizing enzyme choline acetyltransferase, In contrast, the mRNA encoding for neurexin-I beta, the heterophilic ligand of the AChE-homologous neuronal cell surface protein neuroligin, was drastically lower in embryonic transgenic spin al cord than in controls, Postnatal cessation of these dual transcript ional responses was followed by late-onset deterioration in neuromotor performance that was associated with gross aberrations in neuromuscul ar ultrastructure and with pronounced amyotrophy. These findings demon strate embryonic feedback mechanisms to neuronal AChE overexpression t hat are attributable to both cholinergic and cell-cell interaction pat hways, suggesting that embryonic neurexin I beta expression is concert ed in vivo with AChE levels and indicating that postnatal changes in n euronal AChE-associated proteins may be involved in late-onset neuromo tor pathologies.