The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

Abstract

SUMMARYCell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1 + pancreatic progenitor cells. Expression of activated Cdk4 R24C kinase leads to increased Nkx2.2 + and Nkx6.1 + cells and a rise in the number and proliferation of Ngn3 + endocrine precursors, resulting in expansion of the  cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes  cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors.KEY WORDS: Cdk4, E2f1, Ngn3 (Neurog3), Pancreas development, Pdx1, Mouse

Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D

“…However, pRB and E2F family members can control neuronal and pancreatic development by direct regulation of genes such as Ngn3 (Kim and Rane 2011;Tsume et al 2012). Thus, E2F factors could orchestrate stem cell and progenitor differentiation in a diversity of tissues, underlining that cell cycle control of cell fate choice could be a common mechanism between a diversity of progenitors.…”

Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6

“…In a complementary experiment, mice lacking Cdk4 were shown to be relatively healthy with the notable exception of diabetes, due to depletion of pancreatic beta cells (30). More recently it was shown that Cdk4 acts at a very early stage in islet cell development by stimulating the replication of neuroendocrine stem cells (33).…”

Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

“…Several studies have attempted to increase endocrine, and particularly β-cell, proliferation through regulation of cell cycle proteins (37,38). Specifically, deletion of the cell cycle regulator Rb in differentiated β-cells did not significantly alter β-cell mass (22).…”