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.

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.

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 The role of SOX proteins in normal pituitary development

2008 ◽  
Vol 200 (3) ◽  
pp. 245-258 ◽  
Author(s):  
Kyriaki S Alatzoglou ◽  
Daniel Kelberman ◽  
Mehul T Dattani
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Transgenic Animal ◽  
Developmental Abnormalities ◽  
Pituitary Development ◽  
Organ Systems ◽  
Sox Proteins

Pituitary development is a complex process that depends on the co-ordinated spatial and temporal expression of transcription factors and signalling molecules that culminates in the formation of a complex organ that secretes six hormones from five different cell types. Given the fact that all distinct hormone producing cells arise from a common ectodermal primordium, the patterning, architecture and plasticity of the gland is impressive. Among the transcription factors involved in the early steps of pituitary organogenesis are SOX2 and SOX3, members of the SOX family that are emerging as key players in many developmental processes. Studies in vitro and in vivo in transgenic animal models have helped to elucidate their expression patterns and roles in the developing hypothalamo–pituitary region. It has been demonstrated that they may be involved in pituitary development either directly, through shaping of Rathke's pouch, or indirectly affecting signalling from the diencephalon. Their role has been further underlined by the pleiotropic effects of their mutations in humans that range from isolated hormone deficiencies to panhypopituitarism and developmental abnormalities affecting many organ systems. However, the exact mechanism of action of SOX proteins, their downstream targets and their interplay within the extensive network that regulates pituitary development is still the subject of a growing number of studies. The elucidation of their role is crucial for the understanding of a number of processes that range from developmental mechanisms to disease phenotypes and tumorigenesis.

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.

Dosage requirement of Pitx2 for development of multiple organs

Development ◽  
1999 ◽  
Vol 126 (20) ◽  
pp. 4643-4651 ◽  
Author(s):  
P.J. Gage ◽  
H. Suh ◽  
S.A. Camper
Keyword(s):  
Heart Development ◽  
Threshold Level ◽  
The Body ◽  
Null Alleles ◽  
Allelic Series ◽  
Heart Tube ◽  
Rieger Syndrome ◽  
Multiple Organs ◽  
Abdominal Organs ◽  
Left Right Asymmetry

Pitx2 is a homeodomain transcription factor that is mutated in Rieger syndrome, a haploinsufficiency disorder affecting eyes and teeth. Pitx2 also has a postulated role in left-right axis determination. We assessed the requirements for Pitx2 directly by generating hypomorphic and null alleles. Heterozygotes for either allele have eye abnormalities consistent with Rieger syndrome. The ventral body wall fails to close in embryos homozygous for the null allele, leaving the heart and abdominal organs externalized and the body axis contorted. In homozygotes for either allele, the heart tube undergoes normal, rightward looping and the stomach is positioned normally. In contrast, homozygotes for both alleles exhibit right isomerization of the lungs. Thus, Pitx2 is required for left-right asymmetry of the lungs but not other organs. Homozygotes for either allele exhibit septal and valve defects, and null homozygotes have a single atrium proving that a threshold level of Pitx2 is required for normal heart development. Null homozygotes exhibit arrest of pituitary gland development at the committed Rathke pouch stage and eye defects including optic nerve coloboma and absence of ocular muscles. This allelic series establishes that Pitx2 is required for the development of mulitple organs in a dosage-sensitive manner.

scholarly journals Hypothalamic and pituitary development: novel insights into the aetiology

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S3-S14 ◽  
Author(s):  
Daniel Kelberman ◽  
Mehul Tulsidas Dattani
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Types ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Gene Encoding ◽  
Complex Disorders ◽  
Signalling Molecules ◽  
Pituitary Development ◽  
Transgenic Murine Models

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.

Formation of Rathke's pouch requires dual induction from the diencephalon

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4835-4840 ◽  
Author(s):  
N. Takuma ◽  
H.Z. Sheng ◽  
Y. Furuta ◽  
J.M. Ward ◽  
K. Sharma ◽  
...  
Keyword(s):  
Regulatory Gene ◽  
Molecular Genetic ◽  
Homeobox Gene ◽  
Subsequent Development ◽  
Null Mutant ◽  
Rathke’S Pouch ◽  
Rathke's Pouch ◽  
Bmp4 Expression ◽  
Molecular Genetic Evidence

Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, Titf1) in mice results in ablation of the pituitary. Paradoxically, while T/ebp is expressed in the ventral diencephalon during forebrain formation, it is not expressed in Rathke's pouch or in the pituitary gland at any time of embryogenesis. Examination of pituitary development in the T/ebp homozygous null mutant embryos revealed that a pouch rudiment is initially formed but is eliminated by programmed cell death before formation of a definitive pouch. In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable. These data and additional genetic and molecular observations suggest that Rathke's pouch develops in a two-step process that requires at least two sequential inductive signals from the diencephalon. First, BMP4 is required for induction and formation of the pouch rudiment, a role confirmed by analysis of Bmp4 homozygous null mutant embryos. Second, FGF8 is necessary for activation of the key regulatory gene Lhx3 and subsequent development of the pouch rudiment into a definitive pouch. This study provides firm molecular genetic evidence that morphogenesis of the pituitary primordium is induced in vivo by signals from the adjacent diencephalon.

scholarly journals The Genetic Backdrop of Hypogonadotropic Hypogonadism

2021 ◽  
Vol 22 (24) ◽  
pp. 13241
Author(s):  
Anna Szeliga ◽  
Michal Kunicki ◽  
Marzena Maciejewska-Jeske ◽  
Natalia Rzewuska ◽  
Anna Kostrzak ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Hypogonadotropic Hypogonadism ◽  
Reproductive Function ◽  
Primary Amenorrhea ◽  
Posterior Lobe ◽  
Cyclic Activity ◽  
Subsequent Formation ◽  
Rathke’S Pouch ◽  
Pituitary Development ◽  
Rathke's Pouch

The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke’s pouch; second, the migration of Rathke’s pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic–pituitary–ovarian axis and contribute to the development of primary amenorrhea.

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