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.
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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

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Figure 4

FOXA1 is the earliest marker of cyst development.

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FOXA1 is the earliest marker of cyst development. (A–D) SOX2-positive ce...
(A–D) SOX2-positive cells are within the anterior lobe in control and Isl1Prop1KO mutants. SOX2 is detected in some cysts walls at birth (B, n = 5), but not P7 (D, n = 6). (E–H) Minimal FOXJ1 immunostaining was detected in controls (n = 3) and increased in Isl1Prop1KO cyst walls with age (n = 3). (I and J) ISL1+ cells are in the ventral Rathke’s pouch, oral ectoderm, and ventral diencephalon in E11.5 controls (n = 6), but few ISL1+ cells are detected in the Isl1Prop1KO mutant (n = 6). Similar E11.5 ISL1 immunostaining samples are described above. (K–N) FOXA1+ cells are in the oral ectoderm, and a few ISL1+FOXA1+ cells are at the pouch/oral ectoderm separation in E11.5 controls (n = 3), but not in Isl1Prop1KO (n = 5). (O and P) SHH expression in the oral ectoderm of E11.5 controls (n = 8) and Isl1Prop1KO (n = 9). (Q and R) GATA3+ ventral expression in E11.5 controls (n = 3) and Isl1Prop1KO (n = 3). (S and T) CDKN1A+ expression in E11.5 controls (n = 3) and Isl1Prop1KO (n = 6). (U–AA) FOXA1 immunostaining was negative in controls (U, n = 3; W, n = 4; Y, n = 3). FOXA1+ cells line cyst walls in Isl1Prop1KO (V, n = 4; X, n = 6; Z, n = 3; AA, n = 6). (AB) FOXA1 and FOXJ1 stain in cyst walls at 1 year (n = 5). (AC–AF) Cytoplasmic GATA3 immunoreactivity is detected in E18.5 (n = 6) and P0 (n = 6) controls (n = 6), and nuclear staining is present in Isl1Prop1KO (n = 6). (AG–AJ) CDNK1A immunostaining was not detected in E18.5 and P0 controls (n = 3, n = 3), but CDNK1A+ cells were detected in Isl1Prop1KO (inset, n = 6, n = 3). Scale bars: 50 μm (A–H, I–T, and U–AJ). Original magnification, ×400 (insets). Sagittal orientation (E11.5, E16.5), coronal orientation (E18.5-after birth). Arrows, immune-positive cells; arrowheads, immune-negative.