Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Abstract

Heterozygous mutations in the human POU-homeobox TCF2 (vHNF1, HNF1␤) gene are associated with maturity-onset diabetes of the young, type 5, and abnormal urogenital tract development. Recently, pancreas atrophies have been reported in several maturity-onset diabetes of the young type 5 patients, suggesting that TCF2 is required not only for adult pancreas function but also for its normal development. Tcf2-deficient mice die before gastrulation because of defective visceral endoderm formation. To investigate the role of this factor in pancreas development, we rescued this early lethality by tetraploid aggregation. We show that TCF2 has an essential function in the first steps of pancreas development, correlated with its expression domain that demarcates the entire pancreatic buds from the earliest stages. Lack of TCF2 results in pancreas agenesis by embryonic day 13.5. At earlier stages, only a dorsal bud rudiment forms transiently and expresses the transcription factors Ipf1 and Hlxb9 but lacks the key transcription factor involved in the acquisition of a pancreatic fate, Ptf1a, as well as all endocrine precursor cells. Regional specification of the gut also is perturbed in Tcf2 ؊/؊ embryos as manifested by ectopic expression of Shh and lack of Ihh and Ipf1 in the posterior stomach and duodenum. Our results highlight the requirement of Tcf2 for ensuring both accurate expression of key regulator molecules in the stomach-duodenal epithelium and proper acquisition of the pancreatic fate. This study provides further insights into early molecular events controlling pancreas development and may contribute to the development of cell-replacement strategies for diabetes.diabetes MODY5 ͉ homeodomain transcription factor ͉ pancreas development ͉ gut regionalization ͉ tetraploid aggregation I n mammals, the pancreas emerges as ventral and dorsal evaginations from the foregut-midgut junction that subsequently fused to form a complex organ. The signaling molecule Sonic Hedgehog (SHH) demarcates a molecular boundary between the prepancreatic endoderm and adjacent stomach and duodenal anlagen and exerts an inhibitory action on pancreas development (1-3). Genetic studies in mice have identified a hierarchical regulatory network involved in pancreas morphogenesis, with significant and sequential differences between ventral and dorsal pancreas. In the mouse, the dorsal bud appears at embryonic day 9.5 (E9.5) concomitantly with the first differentiated glucagon-producing cells. The homeobox gene Ipf1(Pdx1) is expressed before and during this budding, and all pancreatic cell types derive from IPF1 ϩ progenitors (4, 5). However, in Ipf1-deficient mice, pancreas development is arrested after budding (6, 7), implying that other factors promote pancreas specification. Recently, the transcription factor Ptf1a (P48) has been shown to be essential for the acquisition of a pancreatic fate by undifferentiated ventral foregut endoderm, being required for the specification of the ventral pancreas and robust outgrowth of the dorsal bud. In its a...

Pancreas organogenesis: From bud to plexus to gland

“…In the absence of HNF1b, there is the transient formation of a dorsal pancreas ud that expresses Pdx1 and Mnx1, but these progenitors fail to expand. Similar to Ptf1a-null mice, the ventral bud is absent in HNF1b mutants (Haumaitre et al, 2005). The observation that Ptf1a expression is lost from HNF1b-null pancreas suggests the inability to enter the pancreas-specific commitment state, and that the absence of ventral bud specification is primarily via the loss of Ptf1a.…”

“…HNF1b is expressed broadly through the foregut-midgut region at E8, and in the liver and both pancreas anlagens at E9.5 (Haumaitre et al, 2005). Solar et al (2009) showed that the early HNF1b-expressing pool is multipotent and can seed all three compartments: acinar, duct, and endocrine.…”

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…For instance, TCF2 defects cause developmental abnormalities in multiple tissues, including kidney and pancreas (Horikawa et al, 1997;Haumaitre et al, 2005), and Bluteau et al (2002) identified biallelic mutations of TCF1 in hepatic adenomas (Bluteau et al, 2002). Subsequently, mutations of TCF1 also were found in colorectal cancer with MSI (Laurent-Puig et al, 2003) and endometrial tumours (Rebouissou et al, 2004), while Rebouissou et al (2005) also identified mutations of TCF2 in renal carcinomas.…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…[62][63][64][65] At e9.5, Hnf1b mutant mice lacked the ventral bud but a transient dorsal bud was present with temporal expression of Pdx1 and Hb9 (Table 1). 66 Later by e13.5, pancreatic agenesis presented with a phenotype similar to Ptf1a deficiency. 66 Additionally, Hnf1b binding sites were identified on the Ptf1a promoter, suggesting a direct regulatory relationship.…”

“…66 Later by e13.5, pancreatic agenesis presented with a phenotype similar to Ptf1a deficiency. 66 Additionally, Hnf1b binding sites were identified on the Ptf1a promoter, suggesting a direct regulatory relationship. 66 Between e11.5-13.5, Hnf1b C cells in the trunk compartment were precursors of acinar, duct and endocrine cells.…”