Rathke’s cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors
Michelle L. Brinkmeier, … , Flávio S.J. de Souza, Sally A. Camper
Michelle L. Brinkmeier, … , Flávio S.J. de Souza, Sally A. Camper
Published May 26, 2020
Citation Information: J Clin Invest. 2020;130(8):4501-4515. https://doi.org/10.1172/JCI136745.
View: Text | PDF
Research Article Development Genetics

Rathke’s cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors

Abstract

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.

Authors

Michelle L. Brinkmeier, Hironori Bando, Adriana C. Camarano, Shingo Fujio, Koji Yoshimoto, Flávio S.J. de Souza, Sally A. Camper

×

Figure 1

ISL1 expression in pituitary progenitor cells is important for growth and morphology.

Options: View larger image (or click on image) Download as PowerPoint
ISL1 expression in pituitary progenitor cells is important for growth an...
(A–D) ISL1 immunostaining reveals ventral expression in Rathke’s pouch and oral epithelium at E10.5 (n = 2) and E11.5 (n = 7) (arrows), ventral expression at E16.5 (n = 2), and expression in the marginal zone and parenchyma at P3 (n = 3). (E and F) ISL1 costains with PROP1 at P3 (n = 2) and SOX2 at P7 (n = 2). Insets show marginal zone (D–F). (G–L) H&E staining from control and Isl1Prop1KO pituitaries at E11.5 (control, n = 7; Isl1Prop1KO, n = 10), E13.5 (control, n = 4; Isl1Prop1KO, n = 4), and E14.5 (control, n = 3; Isl1Prop1KO, n = 5) reveals dysmorphology in anterior (arrows) and intermediate lobes (arrowheads). (M and N) CCND1 immunostaining of control (n = 4) and Isl1Prop1KO (n = 6) pituitaries at E11.5 (bracket denotes negative region). (O and P) Immunostaining for cleaved caspase-3 detected apoptotic cells in E11.5 control (n = 6) and Isl1Prop1KO mutants (n = 13) at normal (arrows) and ectopic sites (arrowheads). (Q) Size of Rathke’s pouch (RP) was normalized to head size and displayed as percentage. Isl1Prop1KO (M, n = 10; range 0.28%–0.54%) was significantly smaller than controls (C, n = 7; range 0.45%–0.62%) based on Student’s t test, 1-tail distribution, 2-sample unequal variance. **P < 0.01. (R and S) H&E staining of control (n = 4) and Isl1Hesx1KO (n = 4) pituitaries at E11.5 confirm dysmorphology. (T–W) CCDN1 (control, n = 2; Isl1Hesx1KO, n = 3) and cleaved caspase-3 (control, n = 2; Isl1Hesx1KO, n = 3) expression confirm abnormal growth. (X and Y) H&E staining of control (n = 3) and Isl1Prop1KO pituitaries (n = 3) reveals multiple cysts at P3 in mutants (arrows). (Z and AA) H&E staining of control (n = 2) and Isl1Hesx1KO pituitaries (n = 2) reveals cyst formation at P0 (arrows). Scale bars: 50 μm (A–P, R–W); 100 μm (X–AA). Original magnification, ×400 (insets).