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Understanding the factors that govern human forebrain regionalization along the dorsal-ventral and left-right (L-R) axes is likely to be relevant to a wide variety of neurodevelopmental and neuropsychiatric conditions. Recent work in lower vertebrates has identified several critical signaling molecules involved in embryonic patterning along these axes. Among these are the Wingless-Int (WNT) proteins, involved in the formation of dorsal central nervous system (CNS) structures, as well as in visceral L-R asymmetry. We examined the expression of WNT2b and WNT7b in the human brain, because these genes have highly distinctive expression patterns in the embryonic mouse forebrain. In the human fetal telencephalon, WNT2b expression appears to define the cortical hem, a dorsal signaling center previously characterized in mouse, which is also confirmed by BMP7 expression. In diencephalon, WNT2b expression is restricted to medial dorsal structures, including the developing pineal gland and habenular nucleus, both implicated in CNS L-R asymmetry in lower organisms. At 5 weeks gestation, WNT7b is expressed in cerebral cortical and diencephalic progenitor cells. As the cortical plate develops, WNT7b expression shifts, demarcating deep layer neurons of the neocortex and the hippocampal formation. Spatial and temporal expression patterns show startling similarity between human and mouse, suggesting that the developmental roles of these WNT genes may be highly conserved, despite the far greater size and complexity of the human forebrain.

In situ hybridization was used to map spatiotemporal expression patterns of the four known intronless POU-III transcription factor genes Brn-1, Brn-2, Brn-4, and Tst-1 in the developing rat forebrain vesicle, beginning on embryonic day 10. The results indicate that the proliferation layers (ventricular and subventricular) and mantle layer of the forebrain neural tube each display a strikingly unique pattern of regionalized POU-III expression. Within a particular region, or layer within a region, none to all four of the mRNAs may be detected, and during development a particular mRNA in a particular region displays one of five expression patterns, or a combination of these patterns, which may be described as conserved, lost, transient, acquired, or redeployed expression. In the developing brain as a whole, Brn-1 and Brn-2 early on display somewhat different spatial expression patterns that converge to essential identity in the adult, whereas Brn-4 expression is initially broad and becomes much more restricted in the adult, and Tst-1 expression expands greatly through development. Usually, though not always, expression patterns tend to correlate with major histological features in the forebrain (often internal or external sulci associated with proliferation zones), and little evidence for waves of expression moving through the whole forebrain over time was obtained. Thus, clear differences in hybridization intensity often are observed between the cerebral cortex, basal telencephalic nuclei, hypothalamus, ventral thalamus, dorsal thalamus, and pretectal region. In contrast, transverse bands of hybridization extending from the roof to the floor of the forebrain, corresponding to proposed neuromeres, were not observed with these probes. The results suggest that POU-III transcription factors help define specific regions in the early neuroepithelium as well as different cellular phenotypes in the ventricular, subventricular, and mantle layers of specific regions later in development. Thus, the functions of these regulatory proteins may be different in proliferating neuroepithelial cells, young neurons, and mature neurons and appear to be region-specific.