Nicotine Abolishes the Hypoxic Induction of Vegf in Human Microvascular Endothelial Cells

Abstract

Primary microcephaly (OMlM 251200) is an autosomal recessive neurodevelopmental condition in which there is a global reduction in cerebral cortex volume to a size comparable with that of early hominids. This marked reduction in human brain size (e.g. 430g compared with 1450g in the normal adult) raises the question as to whether genes mutated in microcephaly may provide insights into the mechanisms by which brain size has dramatically increased during evolution. We have identified a gene encoding a BRCAl C-terminal domaincontaining protein, mutated in MCPHl families sharing an ancestral 8p23 haplotype. This gene, microcepkalin, is expressed in the developing cerebral cortex of the fetal brain. Sequence homologies suggest a role in DNA repair or cell cycle regulation. The microceplialin gene has been present throughout vertebrate evolution, and we have characterised fish, rodent and primate orthologs. All contain the angiopoeifin-2 gene on the reverse strand in intron 12 of microcephalin. Protein sequence homology is strikingly low, with 57% sequence identity between mouse and human orthologs (c.f. mean human-mouse protein sequence identity, 85%; angiopoeitin-2, 88%). This suggests the potential for significant functional changes during recent evolution. Further studies of microcephalin in different species should provide insights into the regulation of cortical neural cell number, potentially aid understanding of neural progenitor/stem cell regulation and shed light on the evolution of the cerebral cortex.