Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum

Abstract

Within the cerebral and cerebellar cortices, neurons are organized in layers that segregate neurons with distinctive morphologies and axonal connections, and areas or regions that correspond to distinct functional domains. To explore the molecular underpinnings of pattern formation in layered regions of the CNS, we have characterized the patterns of expression of two homeodomain genes, Otx1 and Otx2, by in situ hybridization during embryonic and postnatal development in the rat. Otx1 and Otx2 are vertebrate homologs of the Drosophila gap gene orthodenticle, and are expressed during the development of the murine CNS (Simeone et al., 1992). Here we report that Otx1 mRNA is expressed in a subpopulation of neurons within cortical layers 5 and 6 during postnatal and adult life. This gene is also expressed by the precursors of deep-layer neurons within the developing cerebral ventricular zone, but is apparently downregulated by the progenitors of upper-layer neurons; Otx1 is never expressed by the neurons of layers 1–4. The spatial and temporal patterns suggest that Otx1 may play a role in the specification or differentiation of neurons in the deep layers of the cerebral cortex. Within the cerebellum, mRNAs for Otx1 and Otx2 are found within the external granular layer (EGL), but in three spatially distinct domains. During postnatal development, Otx1 is expressed within anterior cerebellar lobules; Otx2 mRNA is localized posteriorly, and a region of overlap in mid-cerebellum defines a third domain in which both genes are expressed. The boundaries of Otx1 and Otx2 expression correspond to the major functional boundaries of the cerebellum, and define the vestibulocerebellum, spinocerebellum, and pontocerebellum, respectively. Spatially restricted patterns of hybridization are observed early in postnatal life, at times that correspond roughly to the invasion of spinal and pontine afferents into the cerebellum (Arsenio-Nunes and Sotelo, 1985; Mason, 1987). These results raise the possibility that Otx1 and Otx2 play a role in cerebellar regionalization during early development.

The determination of projection neuron identity in the developing cerebral cortex

“…For example, progenitors in the VZ at early stages of corticogenesis express a number of transcription factors (such as Fezf2, Otx1, Sox2, and Emx2) that are maintained by their progeny as young neurons populate the deep layers [11][12][13][14]. However, at middle stages of neurogenesis, as progenitors begin to produce the neurons of layers 4 through 2, the cells undergo a series of interesting cellular and molecular alterations.…”

“…Some of these (e.g., Otx1) show a clear correlation in expression between early progenitors and deep layer neurons, but have no obvious functional role in the establishment of neuronal fates or identities [13,29]. However, others do appear to play important roles in fate determination.…”

Insights into the urbilaterian brain: conserved genetic patterning mechanisms in insect and vertebrate brain development

“…During corticogenesis, Otx1 expression is maintained in the ventricular zone of the cortical anlage, but decreases as upper layer neurons are generated. By this time, postmigratory neurons of layers 5 and 6 progressively start to express Otx1, whereas later differentiated neurons of upper layers 1-4 remain devoid of Otx1 expression (Frantz et al, 1994). Otx1 is also expressed at early embryonic stages in precursor structures of sense organs, such as the a) In the fly the otd gene is expressed throughout most of the protocerebrum and the anterior part of the deutocerebrum.…”

Stem Cells in Neurodevelopment and Plasticity

“…Neurons progressively migrate to their target sites, some of them carrying with them the legacy of transcription factors expressed by their progenitors. For example, the homeodomain gene Otx1 , expressed in a decreasing antero-posterior gradient by cortical progenitor cells, continues to be expressed by their cortical neuron progenies (Simeone et al 1992;Frantz et al 1994 Tropepe et al 2001). Neural fate is suppressed by Transforming Growth Factor ␤ (TGF-␤ ) signaling, which actively promotes epidermal differentiation.…”

“…Possible molecular mechanisms are the downregulation of critical growth factors and homedomain genes that may be necessary for the generation or survival of neuronal progenitors from stem cells. A typical example is Otx1 and Fgf2 in the cerebral cortical neuroepithelium (Frantz et al 1994;Vaccarino et al 1999a;Vaccarino 2000).…”