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

TY - JOUR

T1 - Growth Factor Independence-1 (Gfi1) Is Required for Pancreatic Acinar Unit Formation and Centroacinar Cell Differentiation

AU - Qu, Xiaoling

AU - Nyeng, Pia

AU - Xiao, Fan

AU - Dorantes, Jorge

AU - Jensen, Jan

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.jcmgh.2014.12.004

DO - 10.1016/j.jcmgh.2014.12.004

M3 - Journal article

C2 - 28247862

SN - 2352-345X

VL - 1

SP - 233-247.e1

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

IS - 2

ER -