Snail2, a mediator of epithelial-mesenchymal transitions, expressed in progenitor cells of the developing endocrine pancreas

Abstract

The mammalian pancreas develops by the expansion and morphogenesis of the epithelial cells of the foregut endoderm via the sequential activation of transcription factors that direct differentiation into the various pancreatic lineages. Implicit in this growth and differentiation are the temporal and spatial processes of cell migration and three-dimensional organization, which cooperate to form a properly functioning organ. In many organ systems, such as the kidney, heart, and neural crest derivatives, migration and tissue morphogenesis is accomplished by the transient conversion of stationary epithelial cells to migratory mesenchymal-like cells in a process known as epithelial-mesenchymal transition (EMT). We report the identification of the expression of the transcription factor Snail2/ Slug, a known inducer of EMT and cell movement, in both the endocrine and exocrine cells of the developing mouse pancreas. Snail2 is expressed in Neurogenin3-positive endocrine progenitor cells, and expression is maintained during endocrine cell differentiation where it becomes increasingly restricted to the insulin-producing beta cells and somatostatin-producing delta cells. In the adult pancreas, the expression of Snail2 is maintained at low but detectable levels in all beta cells, indicating a latent role for Snail2 in the mature islet. These findings of Snail2 expression during endocrine pancreas development are relevant to the recent evidence demonstrating the involvement of EMT in the expansion of human islet tissue in vitro. EMT-like events appear to be involved in the development of the mammalian pancreas in vivo.

Pancreas organogenesis: From bud to plexus to gland

“…The direct targets of Ngn3 include NeuroD1/ Beta2, Pax4, Arx, Insm1, Rfx6, Nkx2.2, Myt1, and Snail2/Slug (Huang et al, 2000;Smith et al, 2003Smith et al, , 2004Smith et al, , 2010Watada et al, 2003;Mellitzer et al, 2006;Wang et al, 2007;Rukstalis and Habener, 2007;Soyer et al, 2010) (Fig. 2B).…”

“…A tantalizing suggestion comes from studies of Snail2, a well-known inducer of EMT and cell movement, which was found in scattered cells of the trunk epithelium during the secondary transition. As 80% of Ngn3 HI cells are Snail2 þ , this suggests that endocrine precursors initiate EMT very soon after commitment to endocrine fate (Rukstalis and Habener, 2007). A deeper analysis of Snail2 function in endocrine delamination and any ''epithelial backup effects'' when it is blocked will be required.…”

“…Endocrine cells then become committed from endocrine-biased progenitors present in the trunk epithelial region (this region has also been historically referred to as ''epithelial cord'' or ''primitive duct''). The delaminating endocrine cells go through a currently poorly defined epithelial exit process that is thought to involve an epithelial-to-mesenchymal transition (EMT) (Rukstalis and Habener, 2007). Endocrine cells that leave the epithelium assemble into clustered endocrine islets but often stay in proximity to, even sometimes appearing relatively intimately associated with, one or the other of their parent ducts.…”

Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development

“…Because all pancreatic endocrine cells arise from epithelial progenitors during embryonic development, they must delaminate from the epithelium, migrate in the mesenchyme, and aggregate into clusters. There are some evidences suggesting that newly generated endocrine cells delaminate by achieving an epithelial-to-mesenchymal transition (EMT; Chiang and Melton, 2003;Rukstalis and Habener, 2007;Cole et al, 2009). EMT is a process by which an epithelial cell becomes mesenchymal and which involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties (Thiery et al, 2009;Acloque et al, 2009).…”

“…After embryonic day (E) 14.5 in mouse embryos, it was reported that endocrine cells exhibit low E-cadherin expression and up-regulate N-cadherin, although it is unclear when this switch occurs (Hutton et al, 1993;Johansson et al, 2010). Moreover, Snail2 (previously known as Slug), a zinc finger transcription factor that promotes EMT, was shown to be expressed in the pancreas (Rukstalis and Habener, 2007). After delamination, endocrine cells migrate in the mesenchyme.…”