The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary

Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors

Context: Adult stem cells maintain some markers expressed by embryonic stem cells and express other specific markers depending on the organ where they reside. Recently, stem/progenitor cells in the rodent and human pituitary have been characterized as expressing GFRA2/RET, PROP1, and stem cell markers such as SOX2 and OCT4 (GPS cells). Objective: Our objective was to detect other specific markers of the pituitary stem cells and to investigate whether craniopharyngiomas (CRF), a tumor potentially derived from Rathke's pouch remnants, express similar markers as normal pituitary stem cells. Design: We conducted mRNA and Western blot studies in pituitary extracts, and immunohistochemistry and immunofluorescence on sections from normal rat and human pituitaries and 20 CRF (18 adamantinomatous and two papillary). Results: Normal pituitary GPS stem cells localized in the marginal zone (MZ) express three key embryonic stem cell markers, SOX2, OCT4, and KLF4, in addition to SOX9 and PROP1 and beta-catenin overexpression. They express the RET receptor and its GFRA2 coreceptor but also express the coreceptor GFRA3 that could be detected in the MZ of paraffin pituitary sections. CRF maintain the expression of SOX2, OCT4, KLF4, SOX9, and beta-catenin. However, RET and GFRA3 expression was altered in CRF. In 25% (five of 20), both RET and GFRA3 were detected but not colocalized in the same cells. The other 75% (15 of 20) lose the expression of RET, GFRA3, or both proteins simultaneously. Conclusions: Human pituitary adult stem/progenitor cells (GPS) located in the MZ are characterized by expression of embryonic stem cell markers SOX2, OCT4, and KLF4 plus the specific pituitary embryonic factor PROP1 and the RET system. Redundancy in RET coreceptor expression (GFRA2 and GFRA3) suggest an important systematic function in their physiological behavior. CRF share the stem cell markers suggesting a common origin with GPS

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGF? and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary

Anales de Edafología y Agrobiología Tomo 48 Número 1-2

Efectos de la lluvia ácida: lixiviación de constituyentes en suelos contaminados. Por F. Romero, C. Elejalde y H. Sabin.-- Evaluación de diversas soluciones extractantes de metales Pesados en suelos como indicadoras de las fomas asimilables para las plantas. Por V. Cala, y J. R. Sanchidrian.-- Adsorción de clorprofan (CIPC) por suelos. II. Adsorción por las distintas fracciones granulométricas. Por G. Dios Cancela, J. A. Guillén Alfaro y S. González Careza.-- Influencia del material de partida del suelo y de los tipos de vegetación sobre las lombrices de tierra. Por S. Mato, D. Trigo y D. J. Díaz Cosin.-- Singularidades edafológicas en la comarca La Plana de Requena - Utiel (Valencia). Por R. Boluda Hernández, V. Andréu Pérez, M. Moraleda Esteve y J. Sánchez Díaz.-- Características de los suelos rojos fersialíticos, en la cuenca de México. Por J. F. Cervantes, G. Alfaro Sánchez y M. Meza Sánchez.-- Rasgos micromorfológicos de una catena de suelos afectados por hidromorfía. Por M. Simón, l. Garcfa y J. Fernández.-- Recuperación edáfica de las escombreras de minas de lignito en Galicia. 1)Caracterización de los materiales estériles. Por Mª C. Leirós de la Peña, F. Gil Sotres, M. Carballas Fernández, C. Codesido López, M. a V. González Sangregorio, S. Seoane Lavandeira y F. Guitián Ojea.-- Recuperación edáfica de las escombreras de minas de lignito en Galicia. 2) Influencia del encalado sobre las formas de acidez. Por F. Gil Sotres, Mª C. Leirós de la Peña, Ma V. González Sangregorio, S. Seoane Lavandeira, C. Codesido López y F. Guitián Ojea.-- Influencia de la dolomita en la naturaleza de los suelos. Por J. González Parra, C. González Huecas y A. López Lajilente.-- Producción frente a contaminación en la utilización agrícola de composts urbanos. Por J. M. Murillo, J. M. Hernández, M. Barroso y R. López.-- Efecto del aporte de molibdeno sobre el crecimiento y actividad nitrato -reductasa de Phaseolus vulgaris L. Por M. a S. Martín Gómez y M. a D. Saco Sierra.-- Aplicación de la voltametría de barrido para la determinación de Cd, Pb y Cu en material vegetal. Por R. González Cuesta.-- Diversos aspectos sobre el papel de la materia orgánica humificada en la formación y estabilización de los agregados del suelo. Por C. Fortún y A. Fortún. Influencia de los inviernos cálidos en la adaptación de variedades de melocotonero. Por J. Egea, T. Berenguer, L. Egea y J. E. GarcíaPeer reviewe