Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation

BACKGROUND & AIMS The genetic specification of the compartmentalized pancreatic acinar/centroacinar unit is poorly understood. Growth factor independence-1 (Gfi1) is a zinc finger transcriptional repressor that regulates hematopoietic stem cell maintenance, pre-T-cell differentiation, formation of granulocytes, inner ear hair cells, and the development of secretory cell types in the intestine. As GFI1/Gfi1 is expressed in human and rodent pancreas, we characterized the potential function of Gfi1 in mouse pancreatic development. METHODS Gfi1 knockout mice were analyzed at histological and molecular levels, including qRT-PCR, in situ hybridization, immunohistochemistry, and electron microscopy. RESULTS Loss of Gfi1 impacted formation and structure of the pancreatic acinar/centroacinar unit. Histologic and ultrastructural analysis of Gfi1-null pancreas revealed specific defects at the level of pancreatic acinar cells as well as the centroacinar cells (CACs) in Gfi1-/- mice when compared with wild-type littermates. Pancreatic endocrine differentiation, islet architecture, and function were unaffected. Organ domain patterning and the formation of ductal cells occurred normally during the murine secondary transition (E13.5-E14.5) in the Gfi1-/- pancreas. However, at later gestational time points (E18.5), expression of cellular markers for CACs was substantially reduced in Gfi1-/- mice, corroborated by electron microscopy imaging of the acinar/centroacinar unit. The reduction in CACs was correlated with an exocrine organ defect. Postnatally, Gfi1 deficiency resulted in severe pancreatic acinar dysplasia, including loss of granulation, autolytic vacuolation, and a proliferative and apoptotic response. CONCLUSIONS Gfi1 plays an important role in regulating the development of pancreatic CACs and the function of pancreatic acinar cells.