Abstract
Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh) whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN).
Highlights
In the last decades, functional experiments in numerous model systems provided crucial insights into the early molecular, cellular, and morphological events underlying forebrain development.They revealed the importance of brain signaling centers: small groups of specialized cells acting as local sources of secreted factors
Studies in chicken revealed that a sequential induction process, initiated by Sonic Hedgehog (Shh) secreted by floor plate cells, underlies the appearance of the shh-expressing line of cells corresponding to the zli [38]
Physical Separation: The Zli as a Tissue Compartment. To fulfill their localized patterning function, cells of a signaling center need to be arranged in a coherent compartment with clear boundaries and lineage restriction
Summary
Functional experiments in numerous model systems provided crucial insights into the early molecular, cellular, and morphological events underlying forebrain development. They revealed the importance of brain signaling centers: small groups of specialized cells acting as local sources of secreted factors. These secreted factors regulate survival, proliferation, and early patterning of neuroepithelial cells and facilitate compartmentalization of the neuroepithelium into functional histological units [1,2,3,4,5,6,7]. We highlight the contribution of signaling pathways to zli formation, discuss implications for the fact that Shh relies on primary cilia for signal transduction and speculate about zli development for the etiology of brain malformations
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