TY - JOUR
T1 - Rathke’s cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors
AU - Brinkmeier, Michelle L.
AU - Bando, Hironori
AU - Camarano, Adriana C.
AU - Fujio, Shingo
AU - Yoshimoto, Koji
AU - de Souza, Flávio S.J.
AU - Camper, Sally A.
N1 - Funding Information:
We thank Robert Lyons and the University of Michigan Advanced Genomics Core and Rich McEachin from the Bioinformatics Core for their help in the planning and analysis of the RNA-Seq experiments. This work was supported by NIH R01 HD034283 (to SAC), the Japan Society for the Promotion of Science Overseas Research Fellowship (to HB), and National Agency for Scientific and Technological Promotion PICT 2013-2171 and CONICET (to FSJDS).
Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene-expression program in the cysts. We confirmed expression of FOXA1, FOXJ1, and stem cell markers in human Rathke’s cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke’s cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke’s cleft cysts and the role of ISL1 in normal pituitary development.
AB - The transcription factor ISL1 is expressed in pituitary gland stem cells and the thyrotrope and gonadotrope lineages. Pituitary-specific Isl1 deletion causes hypopituitarism with increased stem cell apoptosis, reduced differentiation of thyrotropes and gonadotropes, and reduced body size. Conditional Isl1 deletion causes development of multiple Rathke’s cleft-like cysts, with 100% penetrance. Foxa1 and Foxj1 are abnormally expressed in the pituitary gland and associated with a ciliogenic gene-expression program in the cysts. We confirmed expression of FOXA1, FOXJ1, and stem cell markers in human Rathke’s cleft cyst tissue, but not craniopharyngiomas, which suggests these transcription factors are useful, pathological markers for diagnosis of Rathke’s cleft cysts. These studies support a model whereby expression of ISL1 in pituitary progenitors drives differentiation into thyrotropes and gonadotropes and without it, activation of FOXA1 and FOXJ1 permits development of an oral epithelial cell fate with mucinous cysts. This pituitary-specific Isl1 mouse knockout sheds light on the etiology of Rathke’s cleft cysts and the role of ISL1 in normal pituitary development.
UR - http://www.scopus.com/inward/record.url?scp=85089129702&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089129702&partnerID=8YFLogxK
U2 - 10.1172/JCI136745
DO - 10.1172/JCI136745
M3 - Article
C2 - 32453714
AN - SCOPUS:85089129702
VL - 140
SP - 4501
EP - 4515
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 8
ER -