Six3 cooperates with Hedgehog signaling to specify ventral telencephalon by promoting early expression of Foxg1a and repressing Wnt signaling

Abstract

SUMMARYSix3 exerts multiple functions in the development of anterior neural tissue of vertebrate embryos. Whereas complete loss of Six3 function in the mouse results in failure of forebrain formation, its hypomorphic mutations in human and mouse can promote holoprosencephaly (HPE), a forebrain malformation that results, at least in part, from abnormal telencephalon development. However, the roles of Six3 in telencephalon patterning and differentiation are not well understood. To address the role of Six3 in telencephalon development, we analyzed zebrafish embryos deficient in two out of three Six3-related genes, six3b and six7, representing a partial loss of Six3 function. We found that telencephalon forms in six3b;six7-deficient embryos; however, ventral telencephalic domains are smaller and dorsal domains are larger. Decreased cell proliferation or excess apoptosis cannot account for the ventral deficiency. Instead, six3b and six7 are required during early segmentation for specification of ventral progenitors, similar to the role of Hedgehog (Hh) signaling in telencephalon development. Unlike in mice, we observe that Hh signaling is not disrupted in embryos with reduced Six3 function. Furthermore, six3b overexpression is sufficient to compensate for loss of Hh signaling in isl1-but not nkx2.1b-positive cells, suggesting a novel Hh-independent role for Six3 in telencephalon patterning. We further find that Six3 promotes ventral telencephalic fates through transient regulation of foxg1a expression and repression of the Wnt/b-catenin pathway.

Six3 dosage mediates the pathogenesis of holoprosencephaly

“…S6). Similar to the results reported in zebrafish (Carlin et al, 2012), Six3 appears to transiently regulate Foxg1 expression during the early stages of mouse embryonic development.…”

“…catenin signaling pathways during dorsoventral patterning of the telencephalon (Danesin et al, 2009;Sylvester et al, 2013). Briefly, Shh activates foxg1 expression in the ventral forebrain and, in turn, Foxg1 is cell-autonomously required for the specification of the ventral telencephalon; Foxg1 also restricts the dorsal telencephalon by repressing wnt8b expression (Danesin et al, 2009). Carlin et al (2012 showed that, in zebrafish, six3 cooperates with Hh signaling to promote Foxg1 expression during dorsoventral patterning of the telencephalon.…”

“…One possibility is that, as suggested by the zebrafish studies, Six3 and Shh cooperate to regulate Foxg1 expression (Carlin et al, 2012); namely, Six3 gives the anterior neural plate the competence to respond to Shh signaling from the prechordal plate and activates Foxg1 expression. Alternatively, Six3 regulates Foxg1 expression independently of Shh, either directly, as in medaka fish, or through an intermediate player (Beccari et al, 2012).…”

“…Foxg1 controls the growth of the telencephalon by regulating the expression of Fgf8 and Bmp4 (Martynoga et al, 2005). Six3 and Foxg1 also restrict dorsal telencephalon by directly repressing Wnt8b (Danesin et al, 2009;Carlin et al, 2012;Liu et al, 2010), while Six3 cooperation with Shh signaling from the prechordal plate activates Shh expression in the RDVM . Shh signaling from the RDVM subsequently regulates the formation of three signaling centers along the midline of the telencephalon, ensuring the proper patterning and morphogenesis of the telencephalon .…”

Transcriptome analysis reveals determinant stages controlling human embryonic stem cell commitment to neuronal cells

“…5C). In mice, both Pax6 and Six3 genes are essential for the appropriate forebrain patterning (37)(38)(39)(40). As expected, PAX6 and SIX3 centering in the hub generated the most connections with other modules (Fig.…”