Hedgehog signaling is required for pituitary gland development

Development ◽  
2001 ◽  
Vol 128 (3) ◽  
pp. 377-386 ◽  
Author(s):  
M. Treier ◽  
S. O'Connell ◽  
A. Gleiberman ◽  
J. Price ◽  
D.P. Szeto ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Hedgehog Signaling ◽  
Homeobox Gene ◽  
Cell Types ◽  
Oral Epithelium ◽  
Regulatory Sequences ◽  
Rathke’S Pouch ◽  
Rathke's Pouch ◽  
Oral Ectoderm ◽  
Gland Development

Pituitary gland development serves as an excellent model system in which to study the emergence of distinct cell types from a common primordium in mammalian organogenesis. We have investigated the role of the morphogen Sonic hedgehog (SHH) in outgrowth and differentiation of the pituitary gland using loss- and gain-of-function studies in transgenic mice. Shh is expressed throughout the ventral diencephalon and the oral ectoderm, but its expression is subsequently absent from the nascent Rathke's pouch as soon as it becomes morphologically visible, creating a Shh boundary within the oral epithelium. We used oral ectoderm/Rathke's pouch-specific 5′ regulatory sequences (Pitx1(HS)) from the bicoid related pituitary homeobox gene (Pitx1) to target overexpression of the Hedgehog inhibitor Hip (Huntingtin interacting protein) to block Hedgehog signaling, finding that SHH is required for proliferation of the pituitary gland. In addition, we provide evidence that Hedgehog signaling, acting at the Shh boundary within the oral ectoderm, may exert a role in differentiation of ventral cell types (gonadotropes and thyrotropes) by inducing Bmp2 expression in Rathke's pouch, which subsequently regulates expression of ventral transcription factors, particularly Gata2. Furthermore, our data suggest that Hedgehog signaling, together with FGF8/10 signaling, synergizes to regulate expression of the LIM homeobox gene Lhx3, which has been proved to be essential for initial pituitary gland formation. Thus, SHH appears to exert effects on both proliferation and cell-type determination in pituitary gland development.

Pitx2is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 329-337 ◽  
Author(s):  
Hoonkyo Suh ◽  
Philip J. Gage ◽  
Jacques Drouin ◽  
Sally A. Camper
Keyword(s):  
Transcription Factors ◽  
Homeobox Gene ◽  
Threshold Level ◽  
Cell Types ◽  
Allelic Series ◽  
Rieger Syndrome ◽  
Rathke’S Pouch ◽  
Pituitary Development ◽  
Rathke's Pouch ◽  
Multiple Stages

Analysis of an allelic series in mice revealed that the Pitx2 homeobox gene is required at multiple stages of pituitary development. It is necessary for initiating expansion of Rathke’s pouch and maintaining expression of the fetal-specific transcription factors Hesx1 and Prop1. At later stages Pitx2 is necessary for specification and expansion of the gonadotropes and Pit1 lineage within the ventral and caudomedial anterior pituitary. Mechanistically, this is due to the dependence of several critical lineage-specific transcription factors, Pit1, Gata2, Egr1 and Sf1, on a threshold level of PITX2. The related Pitx1 gene has a role in hormone gene transcription, and it is important late in ontogeny for the final expansion of the differentiated cell types. Pitx1 and Pitx2 have overlapping functions in the expansion of Rathke’s pouch, revealing the sensitivity of pituitary organogenesis to the dosage of the PITX family. The model developed for PITX gene function in pituitary development provides a better understanding of the etiology of Rieger syndrome and may extend to other PITX-sensitive developmental processes.

Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo

Development ◽  
1996 ◽  
Vol 122 (1) ◽  
pp. 41-52 ◽  
Author(s):  
E. Hermesz ◽  
S. Mackem ◽  
K.A. Mahon
Keyword(s):  
Homeobox Gene ◽  
Cell Types ◽  
Early Embryo ◽  
Neural Plate ◽  
Specific Cell ◽  
Expression Domain ◽  
Rathke’S Pouch ◽  
Rathke's Pouch ◽  
Prechordal Plate ◽  
Early Expression

We have isolated a new murine homeobox gene, Rpx (for Rathke's pouch homeobox), that is dynamically expressed in the prospective cephalic region of the embryo during gastrulation. Early expression is seen in the anterior midline endoderm and prechordal plate precursor. Expression is subsequently activated in the overlying ectoderm of the cephalic neural plate, suggesting that inductive contact with Rpx-expressing mesendoderm is required for this expression. Subsequently, Rpx expression is extinguished in the mesendoderm while remaining in the prospective prosencephalic region of the neural plate ectoderm. Ultimately, transcripts become restricted to Rathke's pouch, the primordium of the pituitary, which is known to be derived from the most anterior ectoderm of the early embryo. Down regulation of Rpx in the pouch coincides with the differentiation of pituitary-specific cell types. Rpx is the earliest known marker for the pituitary primordium, suggestive of a role in the early determination or differentiation of the pituitary. Since Rpx is expressed so dynamically and so early in the anterior region of the embryo, and since its early expression domain is much more extensive than the region fated to form the pituitary, it is likely that Rpx is involved in the initial determination of the anterior (prechordal) region of the embryo.

scholarly journals Role of PROP1 in Pituitary Gland Growth

2005 ◽  
Vol 19 (3) ◽  
pp. 698-710 ◽  
Author(s):  
Robert D. Ward ◽  
Lori T. Raetzman ◽  
Hoonkyo Suh ◽  
Brandon M. Stone ◽  
Igor O. Nasonkin ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Anterior Pituitary ◽  
Anterior Lobe ◽  
Clinical Findings ◽  
Proliferative Potential ◽  
Rathke’S Pouch ◽  
Rathke's Pouch ◽  
Pituitary Hyperplasia ◽  
Dividing Cells ◽  
Pituitary Hypoplasia

Abstract Mutations in the PROP1 transcription factor gene lead to reduced production of thyrotropin, GH, prolactin, and gonadotropins as well as to pituitary hypoplasia in adult humans and mice. Some PROP1-deficient patients initially exhibit pituitary hyperplasia that resolves to hypoplasia. To understand this feature and to explore the mechanism whereby PROP1 regulates anterior pituitary gland growth, we carried out longitudinal studies in normal and Prop1-deficient dwarf mice from early embryogenesis through adulthood, examining the volume of Rathke’s pouch and its derivatives, the position and number of dividing cells, the rate of apoptosis, and cell migration by pulse labeling. The results suggest that anterior pituitary progenitors normally leave the perilumenal region of Rathke’s pouch and migrate to form the anterior lobe as they differentiate. Some of the cells that seed the anterior lobe during organogenesis have proliferative potential, supporting the expansion of the anterior lobe after birth. Prop1-deficient fetal pituitaries are dysmorphic because mutant cells are retained in the perilumenal area and fail to differentiate. After birth, mutant pituitaries exhibit enhanced apoptosis and reduced proliferation, apparently because the mutant anterior lobe is not seeded with progenitors. These studies suggest a mechanism for Prop1 action and an explanation for some of the clinical findings in human patients.

scholarly journals Ontogeny of Adenohypophyseal Cells, Pituitary Gland Development and Structure in Adults of Astyanax Lacustris (Teleostei, Characidae): an Emerging Neotropical Fish Species

2021 ◽  
Author(s):  
Giovana Souza Branco ◽  
Lázaro Wender O. De Jesus ◽  
Monica Cassel ◽  
Chayrra Chehade ◽  
Marília de Paiva Camargo ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Early Development ◽  
Fish Species ◽  
Cell Types ◽  
South American ◽  
Neotropical Fish ◽  
Future Studies ◽  
Commercial Importance ◽  
Gland Morphogenesis ◽  
Gland Development

Abstract Pituitary gland morphogenesis of the adenohypophyseal (AH) cells of Astyanax lacustris are presented herein. This Characiformes species show great ecological and commercial importance, and it has been increasingly used as a biological model. The first AH cells of A. lacustris were detected at 1 dah by the immunostaining of PRL producing cells. The morphology of the gland presented changes in shape throughout the development, starting elongated but more oval at the end. The neurohypophysis was differentiated at 3 dah, along with the identification of ACTH, MSH, TSH, and FSH producing cells. Identification of the immunoreactive cells to anti-LH, anti-SL, and anti-GH antibodies occurred at 5 dah. At 20 dah, an increase in pituitary size and the presence of the pituitary stalk were observed. At 60 dah, the pituitary already had the same shape seen in adults. The ontogeny of adenohypophyseal cells in A. lacustris corroborates the heterogeneity in the appearance of these cell types in teleosts and suggests that these hormones actively participate during the early development of this species. Our results collaborate with the understanding of the morphogenesis of the hypothalamic-pituitary-gonadal axis in South American teleosts, showing essential data for the development of future studies related to pituitary morphophysiology.

Regulatory sequences driving expression of the sea urchin Otp homeobox gene in oral ectoderm cells

2007 ◽  
Vol 7 (1-2) ◽  
pp. 124-130 ◽  
Author(s):  
Vincenzo Cavalieri ◽  
Maria Di Bernardo ◽  
Giovanni Spinelli
Keyword(s):  
Sea Urchin ◽  
Homeobox Gene ◽  
Regulatory Sequences ◽  
Oral Ectoderm

scholarly journals SAT-291 SIX3 Is Essential for Hypothalamic and Pituitary Development

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hironori Bando ◽  
Michelle L Brinkmeier ◽  
Frederic Castinetti ◽  
Peter Gergics ◽  
Amanda H Mortensen ◽  
...  
Keyword(s):  
Bmp Signaling ◽  
Pituitary Hormone ◽  
Homeodomain Protein ◽  
Loss Of Function ◽  
Shh Signaling ◽  
Rathke’S Pouch ◽  
Pituitary Development ◽  
Rathke's Pouch ◽  
Oral Ectoderm ◽  
Congenital Hypopituitarism

Abstract The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over causal 30 genes have been identified, including six in the SHH signaling pathway. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. It activates SHH signaling and represses BMP signaling. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified a rare, heterozygous variant in SIX3 in two children with neonatal GH and TSH deficiency and stalk interruption, p.P74R. Using transient transfection in 3T3 cells, we demonstrated that the variant reduced the ability of SIX3 to transactivate the SHH enhancer and promoter of FOXG1, suggesting that the variant could be deleterious. To understand the role of SIX3 in hypothalamic and pituitary development we used Nkx2.1-cre and Prop1-cre to delete Six3 in mice. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination or expression of Fgf10 or Tcf7l2 at e11.5. The oral ectoderm invaginated in mutants, but no definitive Rathke’s pouch formed. There was no evidence of Lhx3 expression and only trace amounts of Pitx1, indicating that pituitary induction failed due to the lack of Six3 in the developing hypothalamus. Similarly, disruption of Six3 expression in Rathke’s pouch using Prop1-cre ablated pituitary development. Together, these data reveal essential roles of Six3 in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities.

scholarly journals SAT-288 Pituitary Developmental Defects Caused by Haploinsufficiency for the Transcription Factor SIX3 Are Worsened by POU1F1 Deficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Michelle Brinkmeier ◽  
Sally Ann Camper
Keyword(s):  
Transcription Factor ◽  
Pituitary Gland ◽  
Clinical Features ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Loss Of Function ◽  
Pituitary Hormone Deficiency ◽  
Rathke’S Pouch ◽  
Rathke's Pouch ◽  
Vasopressin Neurons

Abstract Advances in genomic technologies are revolutionizing the practice of medicine by delivering molecular diagnoses that can be informative for prognosis and treatment of genetic disorders. Most of the known genetic causes of multiple pituitary hormone deficiency have been investigated as monogenic disorders. It can be challenging to predict clinical features from genetic data, as loss of function mutations in some genes can present with a spectrum of phenotypes ranging from craniofacial abnormalities, intellectual disability, and neurosensory and neuroendocrine defects to pituitary hormone deficiency with no other abnormalities. Although maternal exposures could be contributing factors, the contribution of rare, deleterious variation in other genes is a likely contributor. In humans, loss of function mutations in the transcription factor SIX3 cause variable, autosomal dominant holoprosencephaly with incomplete penetrance, and mouse models recapitulate some of the clinical features. Because Six3 and Pou1f1 gene expression patterns overlap in pituitary development, we hypothesized that doubly heterozygous mice (Six3+/-; Pou1f1+/dw) might have pituitary anomalies not present in singly heterozygous mice. We intercrossed Six3+/- and Pou1f1+/dw mice to produce doubly heterozygous animals. At e11.5, both Six3+/- and Six3+/-; Pou1f1+/dw exhibited abnormal morphology of the developing infundibulum and Rathke’s pouch, although ventral diencephalon expression of Tle4, Fgf10, and Nkx2.1 appeared normal. Both newborn Six3+/- and Six3+/-; Pou1f1+/dw littermates had abnormal pituitary gland morphology that resembled that of Aes-/-. AES is a co-repressor that interacts with SIX3. Specification of vasopressin neurons and anterior lobe hormone cell types appeared normal. Mice of all genotypes were born in expected Mendelian ratios (N=144, p=0.49), and there were no significant differences in body weight at 3 wks. A portion of the Six3+/- and doubly heterozygous mice developed hydrocephalus, exhibited failure to thrive, and died (6-9% of N=82, 85, respectively). At 6 wks, 25% (N=61) of the Six3+/-; Pou1f1+/dw animals exhibited striking pituitary dysmorphology in which the rostral aspect of the pituitary penetrated the palate. This was not observed in single heterozygotes. These results reveal that haploinsufficiency for Six3 affects Rathke’s pouch formation, resulting in pituitary gland dysmorphology in and around the stem cell niche. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease and highlighting phenotypic variability. Genetically engineered mice provide an excellent tool for assessing the possibility of gene-gene interactions that could enhance the severity of hypopituitarism and associated craniofacial development.

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