Geminin Is Required for Epithelial to Mesenchymal Transition at Gastrulation

Abstract

Geminin is a multifunctional protein previously suggested to both maintain the bone morphogenetic protein inhibition required for neural induction and to control cell-cycle progression and cell fate in the early embryo. Since Geminin is required in the blastocyst on E3.5, we employed shRNA to examine its role during postimplantation development. Geminin knockdown inhibited the epithelial to mesenchymal transition (EMT) required at gastrulation and neural crest delamination, resulting in anterior-posterior axis and patterning defects, while overexpression promoted EMT at both locations. Geminin was negatively correlated with expression of E-cadherin, which is critically involved in controlling epithelial architecture. In addition, Geminin expression level was correlated with Wnt signaling and expression of the Wnt target gene Axin2 and with Msx2, and negatively correlated with the expression of Bmp4 and Neurog1 in quantitative reverse transcriptase-polymerase chain reaction analysis of RNAs from individual embryos. These results suggest that in addition to patterning the early embryo, Geminin plays a previously unrecognized role in EMT via its ability to affect Wnt signaling and E-cadherin expression.

Foxd4 is essential for establishing neural cell fate and for neuronal differentiation

“…Like Foxd4, when Gmnn is depleted ESCs still proliferate and form colonies, and over-expression upregulates NSC and NPC genes (Yellajoshyula et al, 2011). Loss of Gmnn in mouse embryos can reduce the numbers of NPCs and either reduce or increase differentiated neurons depending on the marker assayed (Emmett and O’Shea, 2012; Patterson et al, 2014; Schultz et al, 2011; Spella et al, 2011). These differential effects are likely due to Gmnn’s ability to affect the epigenetic state of NSCs (Caronna et al, 2013; Seo et al, 2007; Yellajoshyula et al, 2012).…”

Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

“…Little is known regarding the molecular mechanism underlying geminin-mediated tumorigenesis and cancer metastasis. Of note, contradictory reports have proposed positive and negative roles for geminin in regulating epithelial-to-mesenchymal transition during development (28,29).…”

Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation

“…Conditional excision of Geminin was previously investigated in the context of neural stem cell maintenance and differentiation (Schultz et al, 2011; Spella et al, 2011), but has not been investigated during the initial formation and patterning of the mammalian neural tube. A recent study used a shRNA knockdown approach to reduce Geminin during gastrulation and identified a role for Geminin during gastrulation (Emmett and O'Shea, 2012). However, these embryos failed to survive to stages needed to determine whether Geminin plays a putative role in neural plate formation and patterning.…”