Abstract
Timing is essential to morphogenesis of the embryonic and fetal nervous system and intricately associated with onset of expression of developmental genes. Mitotic cell cycles are timed. Teratogenic toxins and other adverse influences are teratogenic in the context of timing by interfering with developmental processes. Each of the 3 axes of the neural tube is associated with two opposing genetic gradients. Many neural malformations can be analyzed pathologically as interference with genetic gradients of one or more of the axes, even if the specific genetic mutation is not yet identified. Examples of cerebral malformations closely associated with defective timing are agenesis of forebrain commissures (anterior and hippocampal commissures form 3 weeks before corpus callosum), neuronogenesis and gliogenesis in disorders of the mTOR signaling pathway (time of expression of postmitotic somatic mutation in relation to the 33 mitotic cycles of neuroepithelium determines extent of lesion of focal cortical dysplasia II or hemimegalencephaly), prosencephalic cleavage and eversion (holoprosencephaly; telencephalic flexure for Sylvian fissure), neuromeric disorders of segmentation of the neural tube (deletion of neuromeres; Chiari I), maturation of individual neurons, synaptogenesis (precocious synaptic circuitry in holoprosencephaly; delayed synapse formation in many genetic/metabolic encephalopathies), myelination (delay in many congenital encephalopathies) and neural crest migrations including craniofacial development (facial dysmorphisms in many genetic syndromes and hypertelorism in some cases of callosal agenesis). Timing of relation of genes in cascade or inhibitory genes acting on others is a key element of normal and abnormal morphogenesis.