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

Abstract

SUMMARYThe homeodomain transcription factor Nkx2.2 is essential for pancreatic development and islet cell type differentiation. We have identified Tm4sf4, an L6 domain tetraspanin family member, as a transcriptional target of Nkx2.2 that is greatly upregulated during pancreas development in Nkx2.2 -/-mice. Tetraspanins and L6 domain proteins recruit other membrane receptors to form active signaling centers that coordinate processes such as cell adhesion, migration and differentiation. In this study, we determined that Tm4sf4 is localized to the ductal epithelial compartment and is prominent in the Ngn3 + islet progenitor cells. We also established that pancreatic tm4sf4 expression and regulation by Nkx2.2 is conserved during zebrafish development. Loss-offunction studies in zebrafish revealed that tm4sf4 inhibits a and b cell specification, but is necessary for e cell fates. Thus, Tm4sf4 functional output opposes that of Nkx2.2. Further investigation of how Tm4sf4 functions at the cellular level in vitro showed that Tm4sf4 inhibits Rho-activated cell migration and actin organization in a ROCK-independent fashion. We propose that the primary role of Nkx2.2 is to inhibit Tm4sf4 in endocrine progenitor cells, allowing for delamination, migration and/or appropriate cell fate decisions. Identification of a role for Tm4sf4 during endocrine differentiation provides insight into islet progenitor cell behaviors and potential targetable regenerative mechanisms.

The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and β-cell differentiation

“…The E14.5 Grg3 -/-pancreas has decreased -and -cells but retains ghrelin + clusters as similarly seen in Nkx2.2 -/-embryos (Anderson et al, 2011;Prado et al, 2004). Furthermore, a recent study suggests that a main defect in Nkx2.2 -/-pancreata is the failure of Tm4sf4 repression, which results in a migratory defect of endocrine progenitors (Anderson et al, 2011). It will be interesting to determine whether Grg3 collaborates with Nkx2.2 to repress Tm4sf4 to promote efficient delamination and differentiation of endocrine cells.…”

“…Interestingly, a repressor form of Nkx2.2 that binds Grg3 introduced into the Nkx2.2 -/-mouse is sufficient to rescue -cells, partially rescue -cells and partially restore ghrelin + cells to normal levels (Doyle et al, 2007). The E14.5 Grg3 -/-pancreas has decreased -and -cells but retains ghrelin + clusters as similarly seen in Nkx2.2 -/-embryos (Anderson et al, 2011;Prado et al, 2004). Furthermore, a recent study suggests that a main defect in Nkx2.2 -/-pancreata is the failure of Tm4sf4 repression, which results in a migratory defect of endocrine progenitors (Anderson et al, 2011).…”

Monoclonal Antibody Targeting of the Cell Surface Molecule TM4SF5 Inhibits the Growth of Hepatocellular Carcinoma

“…Tetraspanins, also known as transmembrane 4 superfamily (TM4SF) members, mediate signal transduction events that regulate cell differentiation, activation, growth, and migration (6,7). For example, TM4SF4 regulates endocrine pancreas differentiation and inhibits Rho family of GTPase-activated cell migration and actin organization in a Rho kinase (ROCK)-independent fashion (7).…”

“…For example, TM4SF4 regulates endocrine pancreas differentiation and inhibits Rho family of GTPase-activated cell migration and actin organization in a Rho kinase (ROCK)-independent fashion (7). The diverse activities of tetraspanins seem to be related to their capacity to associate with various molecules, including integrins and other tetraspanins (8,9).…”

Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth <italic>in vitro</italic> and <italic>in vivo</italic>

“…For humans, TM4SF4 is found to be overexpressed in 70% liver cancer tissues and correlates with tumor progression [11]. Moreover, TM4SF4 can regulate endocrine pancreas differentiation and directed cell migration [12]. However, the possibility that TM4SF4 could act as a therapeutic target remains unknown.…”