Neocortical malformation as consequence of nonadaptive regulation of neuronogenetic sequence

Variations in the structure of the neocortex induced by single gene mutatio ns may be extreme or subtle. They differ from Variations in neocortical str ucture encountered across and within species in that these "normal" structu ral variations are adaptive (both structurally and behaviorally), whereas t hose associated with disorders of development are not. Here we propose that they also differ in principle in that they represent disruptions of molecu lar mechanisms that are not normally regulatory to variations in the histog enetic sequence. We propose an algorithm for the operation of the neuronoge netic sequence in relation to the overall neocortical histogenetic sequence and highlight the restriction point of the G1 phase of the cell cycle as t he master regulatory control point for normal coordinate structural variati on across species and importantly within species. From considerations based on the anatomic evidence from neocortical malformation in humans, we illus trate in principle how this overall sequence appears to be disrupted by mol ecular biological linkages operating principally outside the control mechan isms responsible for the normal structural variation of the neocortex. (C) 2000 Wiley-Liss, Inc.