Development of the Cerebral Cortex: IV. Transcription Factors

Abstract

One hundred thousand genes are estimated to lie on the full complement of human chromosomes. Of these, fully one third are thought to be specifically expressed within the cen­ tral nervous system. The proteins encoded by these approx­ imately 30,000 genes are expressed at different developmental periods. Many exert their effects during early brain develop­ ment, while others are expressed only in more mature neurons when specific neurotransmitters or their receptors are required. Finally, another set of genes encode structural and essential cellular proteins, and these genes are expressed con­ tinuously during the life of the neuron. It is important to appreciate how this genetic blueprint unfolds, as disturbances of this process affect the development of the central nervous system. Recently, the mutations for several developmental disorders were found to be in the genes for a family of regu­ latory proteins that are called transcription factors. In this column, the role of transcription factors in regulating gene expression within the developing brain will be reviewed. The basic flow of biological information within any cell is from DNA to RNA to protein. Gene expression can be regulated at a number of steps in this pathway. The first level of control occurs by regulating how often and at what developmental periods a particular gene is transcribed into RNA. This form of regulation is termed transcriptional con­ trol. However, additional levels of control also exist. For example, after the initial transcription of RNA from DNA, the resultant RNA molecule must be processed into a more mature RNA transcript. These mature messages are then transported from the nucleus, where they are synthesized, into the cytoplasm, where they are translated into proteins required by that cell. Regulating the amount of message produced, as well as its life span, affects the amount of pro­ tein that is eventually present. Moreover, once proteins are synthesized, they are often modified by additional mechan­ isms, such as phosphorylation and glycosylation. Control mechanisms have evolved for each of these steps, and their disruption leads to a number of neuropsychiatric disorders, including Waardenburg syndrome, Prader-Willi syndrome, and fragile X syndrome. Transcriptional control of genes is found throughout the animal kingdom. The mechanism lies within the promoter region of a gene, a region that is usually found immediately adjacent to the site at which transcription is initiated. Two fundamental components are required (Fig. 1). The first is the presence of short stretches of DNA within the promoter region. The second component consists of regulatory proteins that recognize these stretches of DNA and bind tightly to them. These proteins are termed transcription factors, and the binding of one or more transcription factors within a promoter region determines whether transcription of that