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WIREs Dev Biol
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Molecular genetic control of cell patterning and fate determination in the developing ventral spinal cord

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Abstract The generation of neuronal diversity in the ventral spinal cord during development is a multistep process that occurs with precise and reproducible spatiotemporal order. The proper functioning of the central nervous system requires that this be carried out with extraordinary precision from the outset. Extrinsic influences such as the secreted Sonic hedgehog (SHH) protein provide positional cues that are read out genetically as specific patterns of gene expression in subsets of dividing progenitors, which is the first overt indication that they have begun to embark upon cell‐type‐specific differentiation programs. Cells generated from these segregated domains will ultimately share similar properties and functions. Recent work illustrates that SHH, which regulates target genes via the GLI transcription factors, directly controls a subset of progenitor fate determinant genes and that both derepression and activation play a role in shaping the differential response to this morphogen. WIREs Dev Biol 2013, 2:419–425. doi: 10.1002/wdev.83 For further resources related to this article, please visit the WIREs website.

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Lineage progression and temporal gene induction patterns in the ventral neural tube. (a) Schematic diagram outlining the lineage derivatives of cells expressing four progenitor genes after patterning has been established at E9.5–10.5 (corresponding to t = 5 in b). Open arrows indicate those progenitor domains in which the expression of the given factor persists until the t = 5 pattern is achieved, whereas solid and dotted arrows indicate those progenitor domains in which it does not. The progenitor domains (p0, etc.) are represented as boxes, which are colored to indicate the factor that is predominant in that domain. Circles represent the neuronal subtypes that are generated from each domain (V0, etc.). The homeodomain transcription factor that identifies each subtype is shown to the right. (b) Establishment of early progenitor patterning over time in relation to dynamic changes in gene expression in specific lineages in the ventral neural tube. Relationship between time points (t = 0, etc.) and embryonic gestational day (E) is approximate. The earliest time, t = 0, represents the basal state of the neural plate prior to ventralization by notochord/node‐derived SHH, whereas t = 5 represents the point at which distinct progenitor domains can first be clearly distinguished and when the pattern of gene expression is well defined. Most or all neural tube cells initially express Pax7 prior to the onset of SHH‐GLI signaling, and expression is progressively downregulated in ventral progenitors over time but persists in dorsal cells (pd6 and more dorsal). Coexpression in progenitor lineages is represented by multicolor spheres, and solid arrows indicate progression within each sublineage. Transient expression is indicated by the absence of color in subsequent lineages; e.g., Nkx2.2 (purple) is activated in the FP, p3, and pMN lineages but persists only in the p3 lineage, whereas Nkx6.2 (orange) is initially expressed in most ventral progenitor domains before becoming restricted to the p1 lineage by t = 5. Dbx1 (light blue) and Dbx2 (light purple) are both initially activated in cells in an intermediate DV position by retinoid signals from paraxial mesoderm.11 Broken arrows in A and red arrows in B indicate that some Dbx1+ and Olig2+ cells may give rise to a small number of pMN or p2 progenitors, respectively.10 ‘pd6’ is the most ventral domain in the dorsal neural tube, identified by Pax7 expression. The FP itself becomes a source of SHH at ∼ t = 4 (indicated by orange ring around FP lineage cells).

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Transcriptional control over SHH‐GLI target gene induction thresholds. (a) The activation of genes that require suppression of GliR activity (i.e., derepression) also depends on the ambient levels of positive coactivators (represented by blue or gray spheres that bind to enhancers/regulatory regions or the promoter, respectively). Gli repressor is shown as a red semi‐sphere. Graph at the top illustrates gene activation threshold changes under three hypothetical conditions: basal (B), weak positive (+), and strong positive (++) influences. (b) The activation of genes requiring GliA induction is influenced by additional factors functioning either positively or negatively. Positive (blue and gray spheres) or negative (orange) factors can bind to regulatory regions also regulated by GliA proteins (red/green sphere). Graph at top illustrates gene activation threshold changes under three hypothetical conditions: basal (B), activator (+), and repressor (−), the latter two shifting the activation thresholds down or up, respectively.

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Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms
Nervous System Development > Vertebrates: Regional Development