Cdc42-Mediated Tubulogenesis Controls Cell Specification

Abstract

Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development

“…We immunostained for the apical marker atypical PKC (aPKC), an essential component of the apical complex. The aPKC colocalizes with mucin at the apical membrane (data not shown, see also Kesavan et al, 2009, for active aPKC). Down-regulation of the aPKC/ Cdc42/Par6 apical complex is known to lead to cell delamination (Georgiou et al, 2008).…”

The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

“…Loss of Cdc42 in the developing pancreas resulted in the failure of multicellular apical polarity establishment and microlumen formation, which was dependent on PKCζ. 36 Furthermore, Cdc42 as well as PKCζ, play important roles during endothelial lumen formation in 3D culture by regulating the polar alignment of vacuoles. 37 Cdc42, Par6B and atypical PKC have also been shown to control lumen formation by regulating mitotic spindle orientation in caco-2 and MDCK cells undergoing morphogenesis in 3D cultures.…”

Pancreas organogenesis: From bud to plexus to gland

“…With respect to the basic tip-trunk regionalization process, one idea is that progenitors that are in close proximity to the mesenchyme and receive a longer integrated exposure to extracellular matrix (ECM) acquire acinar fate, whereas progenitors receiving less mesenchyme exposure have a higher bias towards forming endocrine cells. The pancreatic tubulogenesis process has now been described in both zebrafish and mouse (Yee et al, 2005;Kesavan et al, 2009, Villasenor et al, 2010. Mapping the endocrine specification niches, and monitoring the density and location of endocrine commitment points throughout the remodeling epithelial plexus should provide clues as to the critical influences for the successful replication of this process in ESC being differentiated in vitro.…”

“…The main events in this transition include active proliferation of pancreatic progenitors to generate a stratified epithelium, followed by formation of multiple microlumens and their subsequent coalescence, which serves as the precursor for turning the entire pancreatic primordium, via a plexus intermediate, into a growing epithelial arbor. The first differentiated endocrine cells, mainly glucagon-producing a-cells, begin to appear in the dorsal bud at this phase of development, in a cluster-budding process, rather than by individual delamination of epithelial cells (Pictet et al, 1972;Herrera, 2000;Kesavan et al, 2009;Villasenor et al, 2010). At E11.5, the gut tube begins to undergo its first coiling movements, a rotation that brings the dorsal and ventral buds into proximity for their future conjoining into a single organ.…”