The tetraspanin Tm4sf3 is localized to the ventral pancreas and regulates fusion of the dorsal and ventral pancreatic buds

Abstract

During embryogenesis, the pancreas develops from separate dorsal and ventral buds, which fuse to form the mature pancreas. Little is known about the functional differences between these two buds or the relative contribution of cells derived from each region to the pancreas after fusion. To follow the fate of dorsal or ventral bud derived cells in the pancreas after fusion, we produced chimeric Elas-GFP transgenic/wild-type embryos in which either dorsal or ventral pancreatic bud cells expressed GFP. We found that ventral pancreatic cells migrate extensively into the dorsal pancreas after fusion, whereas the converse does not occur. Moreover, we found that annular pancreatic tissue is composed exclusively of ventral pancreas-derived cells. To identify ventral pancreas-specific genes that may play a role in pancreatic bud fusion, we isolated individual dorsal and ventral pancreatic buds, prior to fusion, from NF38/39 Xenopus laevis tadpoles and compared their gene expression profiles (NF refers to the specific stage of Xenopus development). As a result of this screen, we have identified several new ventral pancreas-specific genes, all of which are expressed in the same location within the ventral pancreas at the junction where the two ventral pancreatic buds fuse. Morpholinomediated knockdown of one of these ventral-specific genes, transmembrane 4 superfamily member 3 (tm4sf3), inhibited dorsalventral pancreatic bud fusion, as well as acinar cell differentiation. Conversely, overexpression of tm4sf3 promoted development of annular pancreas. Our results are the first to define molecular and behavioral differences between the dorsal and ventral pancreas, and suggest an unexpected role for the ventral pancreas in pancreatic bud fusion.

The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration

“…Tm4sf4 is involved in intestinal progenitor cell adhesion and migration during differentiation of intestinal crypt cells (Diosdado et al, 2004;Wice and Gordon, 1995). Recently in Xenopus, Tm4sf3 was described to regulate dorsal and ventral pancreatic bud fusion and ventral bud cell migration, and independently appeared to inhibit ventral b cell differentiation (Jarikji et al, 2009). We believe Tm4sf4 plays a role during endocrine pancreas specification, promoting progenitor cell adhesion to the ductal epithelium and inhibiting migration of the differentiating Ngn3 + population.…”

Xenopus as a Model for GI/Pancreas Disease

“…For example, by producing chimeric embryos where either the dorsal or ventral pancreatic bud was labeled we demonstrated that the ventral pancreatic bud cells migrate extensively into the dorsal bud after fusion while dorsal pancreatic bud cells do not (Fig. 1b) [11••]. By isolating individual dorsal and ventral pancreatic buds we compared their gene expression profiles and identified several new genes involved in regulating cell fate specification and proliferation in the developing pancreas [11, 36, 37].…”

“…By isolating individual dorsal and ventral pancreatic buds we compared their gene expression profiles and identified several new genes involved in regulating cell fate specification and proliferation in the developing pancreas [11, 36, 37]. We showed that the tetraspanin, tm4sf3 , was localized to the ventral pancreas and regulates fusion of the dorsal and ventral buds [11], whereas the RNA binding protein Celf3 controls proliferation in the developing endoderm through translational activation of key cell cycle genes. By producing different fusion proteins between Celf3 and Celf1 we identified the linker region of Celf3 as responsible for the translational enhancement activity on cyclin A2 mRNA [36].…”

“…These experiments revealed that the ventral pancreatic bud cells migrate extensively after fusion, while the dorsal bud cells did not. (Reproduced with permission from Development [11])…”

Functional variants of TSPAN8 are associated with bipolar disorder and schizophrenia

“…Tetraspanins are a family of evolutionarily highly conserved proteins which influence a wide variety of physiologic processes and diseases, among others protein trafficking [Berditchevski and Odintsova, 2007], modulation of immune-signaling complexes [Levy and Shoham, 2005], and cancer [Z€ oller, 2009]. The regulated expression of TSPAN8 (also known as TM4SF3 or CO-029) is important for early development of the pancreas [Jarikji et al, 2009] and TSPAN8 protein abundance is known to be positively correlated with tumor progression , similar to tetraspanins CD151 (TSPAN24) [Yang et al, 2008] or TSPAN1 [Scholz et al, 2009] and opposite to, for example, CD9 (TSPAN29) [De Bruyne et al, 2008] or CD82 (TSPAN27) [Miranti, 2009], whose protein expression is negatively correlated with malignant phenotype. Besides the severe impact of expression changes of TSPAN8 and tetraspanins in general, mutations in TSPAN7 (CD231, TM4SF2) resulting in the amino acid substitution P172H lead to X-linked mental retardation [Zemni et al, 2000;Maranduba et al, 2004].…”