Growth Factor Independence-1 () 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 () 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 / is expressed in human and rodent pancreas, we characterized the potential function of in mouse pancreatic development.

Methods: knockout mice were analyzed at histological and molecular levels, including qRT-PCR, in situ hybridization, immunohistochemistry, and electron microscopy.

Results: Loss of impacted formation and structure of the pancreatic acinar/centroacinar unit. Histologic and ultrastructural analysis of -null pancreas revealed specific defects at the level of pancreatic acinar cells as well as the centroacinar cells (CACs) in  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 pancreas. However, at later gestational time points (E18.5), expression of cellular markers for CACs was substantially reduced in mice, corroborated by electron microscopy imaging of the acinar/centroacinar unit. The reduction in CACs was correlated with an exocrine organ defect. Postnatally, deficiency resulted in severe pancreatic acinar dysplasia, including loss of granulation, autolytic vacuolation, and a proliferative and apoptotic response.

Conclusions: plays an important role in regulating the development of pancreatic CACs and the function of pancreatic acinar cells.