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 3

Isl1 is required for gonadotrope and thyrotrope lineages.

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Isl1 is required for gonadotrope and thyrotrope lineages. (A–D) FOXL2 a...
(A–D) FOXL2 and CGA immunostaining in control (A, n = 3; C, n = 4) and Isl1Prop1KO (B, n = 3; D, n = 4) pituitary glands at E13.5. (E and F) TSH immunostaining in control (n = 3) and Isl1Prop1KO (n = 7) pituitary glands at E16.5.(G and H) NR5A1 immunostaining in E16.5 control (n = 3) and Isl1Prop1KO (n = 3) pituitaries. (I and J) Gata2 ISH in E16.5 pituitaries of control (n = 7) and Isl1Prop1KO (n = 8). (K–N) LH and TSH immunostaining in P3 pituitaries in controls (n = 3) and Isl1Prop1KO (n = 3). (O and P) Quantitation of LH and TSH immunopositive cells per unit area of the pituitary at P0 reveals decreases in gonadotropes (control, n = 5, range = 5.4–14.9; Isl1Prop1KO, n = 4, range = 1.5–7.1) and thyrotropes (control, n = 5, range = 26.7–43.4; Isl1Prop1KO, n = 4, range = 12.1–20.5) in Isl1Prop1KO. (Q–T) E18.5 control and tamoxifen-induced ablation of ISL1 (CAG-Cre-ERT2;Isl1fl/fl) mouse model were immunostained for FSH (control, n = 3; mutant, n = 3) and TSH (control, n = 5; mutant, n = 5). Arrows indicate rare gonadotropes in both types of ISL1-deficient mutants. (U and V) Quantitation of FSH- and TSH-positive cells per unit area revealed decreases in both cell populations in CAG-Cre-ERT2;Isl1fl/fl mutants (FSH, range = 0.14–0.2; TSH, range = 0.2–0.7) relative to controls (FSH, range = 0.8–2.0; TSH, range = 1.3–3.1). (W) Male and female Isl1Prop1KO mice (male, n = 8, range = 6.2–12.6 g; female, n = 11, range = 5.2–13.8g) weigh less than control littermates (male, n = 10, range = 10.5–14.7 g; female, n = 12, range = 10.8–17.7 g) at 3 weeks and have reduced serum T4 (X, control, n = 7, range = 0.94–3.18; mutant, n = 7, range = 0.0–2.33). Scale bars: 50 μm (A–L, N, O, Q–U). Sagittal orientation (A–F, I, J, Q–U), coronal orientation (G, H, K–O). Statistical significance was determined using Student’s t test, 1-tail distribution, 2-sample equal variance (O, P, and U–X). *P < 0.05; **P < 0.01; ***P < 0.001.