Development of the Cerebral Cortex:
V. Transcription Factors and Brain Development

John L.R. Rubenstein, M.D., Ph.D.
J Am Acad Child Adolesc Psychiatry, 37(5):561-562, 1998
As was discussed in the last Development and Neurobiology column (see the April issue of the Journal), transcription factors regulate the expression of proteins that are necessary during the development of specific tissues throughout the body. This is true in the brain as well. Over the past decade, transcription factors that are expressed in regionally restricted patterns within the developing brain have been identified. Often their patterns of expression respect boundaries that delimit major brain subdivisions. For instance, some transcription factor genes are expressed in the developing cerebral cortex (Emx-1 and -2), whereas others are found in the developing basal ganglia (Dlx-1 and -2) (Fig. 1).
Many types of transcription factors are expressed in the brain. Classes of transcription factors are defined on the basis of the amino acid sequences of their DNA binding motifs, which include the homeodomain, helix-loop-helix,
and T box. Relatively little is known about the genes that are regulated by transcription factors. However, through analyses of mice with mutations in these genes, termed “knock-out” mice, we are beginning to understand their roles in controlling the development of particular regions of the brain.
In an effort to determine the function of unknown genes and their protein products, investigators are now able to generate mice that lack the expression of a particular gene. They raise the mice in the laboratory and study the effects that lacking this gene might have on the growth, development, and survival of the animal. A number of such knock-out mouse models have been generated, and some of these will be reviewed in this column as they have been shown to have interesting phenotypes, particularly in the area of hyperactivity and aggression. Similar efforts have been applied to homeobox genes to determine the
 

 

 
Fig. 1 Schematic diagram of embryonic brain organization showing the principal expression domains of Hoxb-1, Dlx-1, Dlx-2, Emx-1, and Emx-2 in the hindbrain, ventral thalamus and basal ganglia, and cerebral cortex, respectively. The expression domains respect boundaries that delineate the transverse and longitudinal subdivisions of the central nervous system. CB = cerebellum; DT = dorsal thalamus; is = isthmus; LGE = lateral ganglionic eminence; LV = lateral ventricle; MGE = medial ganglionic eminence; ME = mesencephalon; p1–6 = prosomeric subdivisions; PT = pretectum; r1–7 = rhombomeric subdivisions; sc = spinal cord; VT = ventral thalamus.

 
contribution these genes make to the development of the brain.
Different classes of homeobox genes tend to be expressed in different regions of the brain and are critical to the development of that specific region. Thus, mutations of the Hox genes disrupt the hindbrain and cause loss of many of the cranial nerves. Mutations in the Engrailed genes disrupt the development of the cerebellum and midbrain. Finally, mutations of the Dlx genes affect differentiation in the basal ganglia, while mutations of the Emx and Otx genes affect the cerebral cortex.
Several generalizations can be made from these studies. The defects in the mutant animals are frequently subtle. This is because there are often several highly related transcription factors in the same tissue, and the closely related gene products are able to take over the function of the mutated gene. Thus, to determine further the effects of these genes on development, investigators are now creating “double knock-outs” in which both genes are removed. When animals have mutations in two of these related genes, they often have much more severe abnormalities. For instance, mutation of Dlx-2 affects one type of interneuron in the olfactory bulb, whereas mutation of both Dlx-1 and Dlx-2 appears to affect all of the interneurons in this region.
Homeobox genes regulate processes ranging from the specification of the identity of brain regions to the growth of these regions to participating in the differentiation of specific cell types or axon tracts. Mutation of Emx-2 eliminates the dentate gyrus of the hippocampus, and mutation of Emx-1 primarily reduces the corpus callosum. In addition, in humans, mutations of Emx-2 result in a type of cerebral cortical malformation called schizencephaly. Thus, these genes are essential for major aspects of brain development, and their absence or mutation causes abnormalities in specific cell types or in the “wiring” within the brain. Mutations or subtle variations in the
 activity level of some of these master control protein deficits are hypothesized to be associated with the more commonly seen neuropsychiatric disorders.

ADDITIONAL READINGS

Anderson S, Qiu M, Bulfone A et al. (1997), Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late-born striatal cells. Neuron 19:27-37

Rubenstein JLR, Shimamura K (1997), Regulation of patterning and differentiation in the embryonic vertebrate forebrain. In: Molecular and Cellular Approaches to Neural Development, Cowan WM, Jessel TM, Zipursky SL, eds. Oxford, England: Oxford University Press, pp 356-390

Yoshida M, Suda Y, Matsuo I et al. (1997), Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124:101-111


Accepted December 3, 1997.
Dr. Rubenstein is Associate Professor of Psychiatry, Center for Neurobiology and Psychiatry, University of California at San Francisco.
Correspondence to Dr. Rubenstein, Nina Ireland Laboratory of Developmental Neurobiology, Center for Neurobiology and Psychiatry, Department of Psychiatry, Box F-0984, 401 Parnassus, University of California at San Francisco, San Francisco, CA 94143-0984.
Dr. Lombroso’s e-mail address is paul.lombroso@yale.edu
0890-8567/98/3705-0561/$03.00/0q1998 by the American Academy of Child and Adolescent Psychiatry.
 

Web Sites of Interest

Bozentrum of the University of Basel: Drosophilia melanogasteri
http://www.biozentrum.unibas.ch/~zellbio/gehring.html

The Interactive Fly: A cyberspace guide to Drosophila genes and their roles in development
http://flybase.bio.indiana.edu:82/allied-data/lk/interactive-fly/aimain/1aahome.htm

Development of Neurobiology

Genetics of Childhood Disorders

Journal of the American Academy of Child and Adolescent Psychiatry