Recent Progress in Hormone Research 58:249-261 (2003)
© 2003 The Endocrine Society
Paired-like Repression/Activation in Pituitary Development
Lorin E. Olson*,
,
Jeremy S. Dasen*,
Bong Gun Ju*,
Jessica Tollkuhn*, and
Michael G. Rosenfeld*,
* Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093-0648
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093-0648
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0648
 |
ABSTRACT
|
|---|
Pituitary gland development is controlled by signals that guide expression of specific combinations of transcription factors that dictate serial determination and differentiation events. One class of factors is paired-like homeodomain factors. Two that have been investigated are the repressor Hex1/Rpx and activator prophet of Pit-1 (Prop-1), which exert selective roles during pituitary development. The opposing actions of these factors provide one aspect of pituitary organogenesis.
|
I. Prophet of Pit-1 (Prop-1)
|
|---|
The anterior pituitary gland develops from a midline structure contiguous with the primordium of the ventral diencephalon (Watanabe, 1982; Couly and Le Douarin, 1988). It integrates signals from the peripheral and central nervous systems, regulating production and secretion of critical regulatory hormones, including growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), gonadotrophins, and adrenocorticotropic hormones by specific cell types (somatotropes, lactotropes, thyrotropes, gonadotropes, and corticotropes, respectively) (Voss and Rosenfeld, 1992). The initial organ determination involves interaction of the primordial stomadeal ectoderm and the neuroepithelium during head folding at embryonic day (e) 8.5 in the mouse (Simmons et al., 1990). The resulting development of Rathke’s pouch (RP) is characterized by expression of multiple homeodomain factors, including the LIM homeodomain factors P-Lim/Lhx3 and Lhx4 (Seidah et al., 1994; Bach et al., 1995; Sheng et al., 1996,1997) and the OTX-related homeodomain factors P-OTX/Pitx1 (Lamonerie et al., 1996; Szeto et al., 1996) and Pitx2 (Gage et al., 1999; Lin et al., 1999; Lu et al., 1999). Restriction of expression of the paired-like homeodomain factor Hesx1/Rpx (Hermesz et al., 1996) to RP also occurs. Following proliferation and early organ expansion, different cell phenotypes arise in a distinct spatial and temporal fashion.
The Snell and Jackson allelic murine dwarf (dw,dwJ) mutations established that the product of the POU domain gene, Pit-1 — expressed in thyrotropes, somatotropes, and lactotropes (Camper et al., 1990; Li et al., 1990) — was required for initial expression of genes encoding secreted hormonal products and receptors for releasing factors. Pit-1 is required later for the continued expression of the Pit-1 gene itself and the proliferation and survival of these three cell types (Godfrey et al., 1993; Li et al., 1993; Rhodes et al., 1993). A mouse genetic defect, referred to as the Ames dwarf (df), was mapped to chromosome 11 (Bartke, 1965; Buckwalter et al., 1991) and proved to be cell-autonomous (Buckwalter et al., 1991), resulting in a hypoplastic anterior pituitary similar to that of the Snell and Jackson dwarfs. In contrast to the complete absence of somatotropes, lactotropes, and thyrotropes in the Snell mouse, the Ames mouse pituitary gland contains between 
1% (Gage et al., 1996b) and 0.001% (Andersen et al., 1995) of the normal complement of somatotropes as well as a few lactotropes and thyrotropes (Gage et al., 1996b). Failure to detect Pit-1 transcripts later in ontogeny (Andersen et al., 1995) is consistent with the hypothesis that the Ames dwarf mutation is epistatic to Pit-1.
The region surrounding the df locus was generally mapped using a CAST/Ei 
C57BL/6J intercross and a Mus spretus C57BL/6J backcross to related CA-repeat markers (Dietrich et al., 1996) to the previously identified locations of the markers Pad-1 and the interleukin (IL) cluster (IL-3, IL-4, and IL-5) (Buckwalter et al., 1991). Four markers provided two proximal and two distal loci that were used to genotype progeny of a large intercross between Cast/Ei and DF/B df/df. The mice were genotyped and phenotypically characterized by size at 4–7 weeks. To obtain more closely linked markers, genetically directed representational difference analysis (GDRDA) (Lisitsyn et al., 1993,1994) was performed using two subsets of F2 and F3 df/df mice with local recombination events, targeting 0.5-centimorgan (cM) and 0.1-cM intervals surrounding df. This technique permitted documentation of a contig. Complementary DNA selection was used to identify the candidate gene, referred to as Prop-1 (Sornson et al., 1996). This gene encodes a paired-like homeodomain factor and a single functional point mutation S83P that decreased DNA binding to the cognate palindromic DNA sites, decreasing the ability to regulate DNA site-dependent genes.
Expression of Prop-1 commences after initial establishment of pituitary structure on e10.5. The expression initially is observed dorsally but subsequently involves most cells in the anterior pituitary gland. The df mutation caused dysmorphogenesis of RP at e12–e12.5, with convolution of the lumen and a failure of expression of the caudomedial Pit-1 lineage. A delayed appearance of gonadotropes was noted but corticotropes appeared as expected. Temporally extended expression of the paired-like homeodomain repressor Hesx1/Rpx1 also was noted. More recently, subtractive hybridization techniques have suggested targets, perhaps including components of the Wnt pathway, which may be under control of Prop-1 (Douglas et al., 2001).
|
II. Rpx/Hesx1 in Pituitary Development
|
|---|
In the anterior neural ridge (ANR), from which the pituitary is derived, a series of transcription factors initially induced in the ANR remain present following the invagination of oral ectoderm to form RP, which subsequently gives rise to the pituitary gland (reviewed in Sheng and Westphal, 1999, and Dasen and Rosenfeld, 2001). Following RP formation, opposing dorsal fibroblast growth factor/bone morphogenetic protein 4 (FGF/BMP4) and ventral Sonic hedgehog (Shh)/BMP2 gradients impart positional and proliferative signals to the pituitary progenitor field, acting to induce combinatorial patterns of transcription factor gene expression. As many mediators of the early signaling events appear capable of acting as either transcriptional activators or repressors, a critical issue has been to define the mechanisms by which these transcriptional codes positively and/or negatively influence downstream gene programs. We examined this with respect to Prop-1 and Rpx/Hesx1.
Multiple transcription factors in pituitary development act in sequential fashion to mediate the appearance of six hormone-producing cell types, which include the homeodomain factors expressed in the anterior neural plate as well as Pitx1/2, Pax6, and Hesx1/Rpx. Upon invagination of the oral ectoderm, the LIM homeodomain factor Lhx3 is induced on e9.5 in the nascent RP and is required for initial organ commitment and growth (Sheng et al., 1996). Subsequently, a second paired-like homeodomain factor, Prop-1, appears on e10.5 and is required for determination of four ventral cell types, including the Pit-1-dependent lineages (somatotropes, lactotropes, and thyrotropes) and gonadotropes (Sornson et al., 1996; Wu et al., 1998). Additional factors — including Pit-1, steroidogenic factor-1 (SF-1), and GATA-2 — are required for cell-type specification within these four lineages (reviewed in Dasen and Rosenfeld, 2001).
Based on the analysis of Ames dwarf (df) mice, which bear a hypomorphic mutation in the homeodomain of the Prop-1 gene, and more severe human mutations (Cogan et al., 1998; Fluck et al., 1998; Wu et al., 1998; Deladoey et al., 1999; Pernasetti et al., 2000), Prop-1 is necessary to activate gene programs required for ventral proliferation and determination of four cell lineages. Hesx1, in contrast, is typical of critical transcriptional repressors that regulate the development of multiple placodally derived anterior structures (Dattani et al., 1998; Martinez-Barbera et al., 2000; Thomas et al., 2001). Attenuation of Hesx1 expression in the developing pituitary coincides with the Prop-1-dependent progression of the pituitary, suggesting that temporal regulation of Hesx1 expression is essential for deployment of the Prop-1-dependent gene activation program (Gage et al., 1996b; Hermesz et al., 1996; Sornson et al., 1996).
|
III. Functional Antagonism Between Hesx1 and Prop-1 in Pituitary Organogenesis
|
|---|
The reciprocal expression and actions of Prop-1 and Hesx1 suggested that their functional interactions might regulate pituitary organogenesis. Hesx1 expression initially marks the oral ectoderm and invaginating RP but then becomes restricted to RP (excluding the ventral rostral tip), where it is maintained until e13.5. In contrast, Prop-1 expression is undetectable until e10.5–e11, becomes maximal during the ventral migration of pituitary lineage precursors beginning at e12.5, and remains detectable between e14.5–e15.5. Following e15.5, expression is maintained only at low levels (Figure 1). Prop-1 and Hesx1 can each bind effectively to a well-described palindromic site (Wilson et al., 1993) as cooperative homodimers or heterodimers, with Prop-1 acting as an activator but not as a repressor (Sornson et al., 1996). Hesx1 acts only as a repressor that can inhibit Prop-1 activation function. Both the N-terminal and homeodomain (HD) regions of Hesx1 can independently act as repressors.
View larger version (96K):
[in this window]
[in a new window]
|
FIG. 1. In situ hybridization showing reciprocal temporal expression of Hesx1 and Prop-1 during the initial phases of pituitary organogenesis. RP indicates Rathke’s pouch.
|
|
Based on the requirement for Hesx1 for development of anterior organs (Dattani et al., 1998; Martinez-Barbera et al., 2000; Thomas et al., 2001), we investigated defects in pituitary development in Hesx1 gene-deleted mice. A striking, although infrequent ( 5%), phenotype (Hesx1-/- mice) was a complete lack of the pituitary gland (Figure 2). Initial thickening of oral ectoderm and minimal activation of Lhx3 initially was observed at e12.5 but the pituitary gland was absent by e18.5. Thus, we tested whether Prop-1 would be capable of phenocopying the pituitary arrest observed in Hesx1-/- mice. When Prop-1 expression was targeted in transgenic mice under control of a promoter expressed only in oral ectoderm, RP, and first branchial arch (Treier et al., 1998,2001), the mice exhibited absent anterior pituitary glands with no initial induction of Lhx3 expression but no abnormalities of developing ventral diencephalon (Figure 3). Thus, either absence of Hesx1 or the premature expression of Prop-1 can block pituitary organogenesis.
View larger version (75K):
[in this window]
[in a new window]
|
FIG. 2. In the most-severe class of Hesx1 mutants, the anterior pituitary (AP) is absent by embryonic day (e) 18.5. Hematoxylin and eosin (H&E) staining. Arrowhead indicates where the gland should be found.
|
|
View larger version (61K):
[in this window]
[in a new window]
|
FIG. 3. Analysis of Pitx1/Prop-1 transgenic founder embryos shows the absence of the AP when Prop-1 is temporally misexpressed. H&E staining. Arrowhead indicates where the developing organ should be found.
|
|
|
IV. Multiple Pituitary Patterning and Growth Defects in Hesx1 Mutant Mice
|
|---|
Unexpectedly, however, the highest percentage of pituitaries with Hesx1 gene deletion resulted in the formation of multiple oral ectoderm invaginations, generating supernumerary pituitary glands with dramatic cellular overproliferation of all the hormone-producing cell types.
Hesx1 mutants exhibited increased domains of Lhx3 and Prop-1 expression (Figure 4). The expression domains of FGF8 and FGF10 in the infundibulum were expanded rostrally, consistent with previous studies demonstrating that Lhx3 expression can be regulated by FGF signaling (Ericson et al., 1998; Treier et al., 1998), indicating that Hesx1 is required for maintaining the proper domains of FGF expression.
View larger version (124K):
[in this window]
[in a new window]
|
FIG. 4. Immunohistochemistry of Hesx1 mutant embryos revealing multiple RPs as invaginations of oral ectoderm expressing the pituitary markers Prop-1 and Lhx3.
|
|
|
V. Hesx1 Recruits the Groucho-related Corepressor Transducin-like Enhancer of Split
|
|---|
The coregulatory apparatus that mediates Hesx1-dependent repression is unknown, although the nuclear receptor corepressor (N-CoR) has been linked to repression mediated by the homeodomain (Laherty et al., 1998; Xu et al., 1998). Another class of corepressors that has been linked to many homeodomain factors is the mammalian orthologues of the Drosophila protein Groucho (reviewed in Chen and Courey, 2000). Groucho is distantly related to the yeast corepressor Tup1, which binds several components of the core transcriptional apparatus — including Srb7, Srb10, Srb11, and Med6 — as well as histone deacetylases (Kuchin and Carlson, 1998; Gromoller and Lehming, 2000; Watson et al., 2000; Wu et al., 2001). Both Groucho and Tup1 contain WD40 repeats, a well-characterized protein-protein interaction domain that has been linked to repression mediated by associations with DNA binding proteins, including transcription factors and histones.
The phenotypes of Hesx1 mutants are consistent with Hesx1 acting as an in vivo transcriptional repressor. Domain mapping revealed that both the N-terminus and homeodomain regions exhibited repression activity. Comparing Hesx1 sequences from several vertebrate species revealed the presence of two conserved motifs outside the homeodomain. The N-terminus contains a motif similar to the eh1 motif originally characterized in the Drosophila repressor engrailed (Smith and Jaynes, 1996) and one similar to the WRPW motif found in several bovine helix-loop-helix (bHLH) proteins (Paroush et al., 1994), both of which are genetically and biochemically linked to the Groucho class of corepressors (Jimenez et al., 1997; Tolkunova et al., 1998). Affinity chromatography revealed a strong and specific interaction between Hesx1 and transducin-like enhancer of split (TLE) corepressors in the mammalian orthologs of Groucho.
Both Hesx1 and TLE1 proved to be coexpressed within RP between e9.5 and e12, with expression becoming rapidly extinguished beginning at e13.5, coincident with the appearance of anterior lobe pituitary cell types. Both the N-terminal tetramerization (Q and GP) domain and WD40 repeat region of TLE were required for interaction with Hesx1/Rpx. Full transcriptional repression required the GP and WD40 domains. Thus, as in the case of the yeast repressor Tup1, the repression and interaction domains appear to be separable, although the WD40 repeat proved to be required for both functions. Finally, repression by the N-terminal domain of Hesx1 was inhibited by 
TLE-1 immunoglobulin G (IgG), indicating that it alone could serve as a component required for Hesx1-dependent repression.
In an attempt to address the functional significance of TLE1 and Hesx1 actions in pituitary development, we generated transgenic mice expressing Hesx1 under the control of a promoter (Pitx1) that targeted misexpression to ventral pituitary cell types, or a promoter alpha glycoprotein hormone subunit (GSU) to maintain Hesx1 expression in specific cell lineages through later stages of development. In these transgenic animals, we observed only minimal phenotypes, characterized by a modest reduction in some cell lineages. In similar experiments, TLE1 expression alone was found to have minimal effects. However, when we generated transgenic animals that maintained expression of both Hesx1 and TLE1 in pituitary development, these mice were characterized by the near-complete absence of ventral anterior pituitary cell types, with an ontogeny and dysmorphogenesis quite similar to that observed in Prop-1-defective Ames dwarf mice (Gage et al., 1996a; Sornson et al., 1996). Thus, there was an absence of Prop-1-dependent cell lineages as determined by loss of expression of the Pit-1, GH, TSHß, and GSU genes, while expression of Prop-1 and proopiomelanocortin (POMC) were maintained (Figure 5A and B). Indeed, the ventral aspect of RP expressed a uniform field of POMC-expressing cells.
View larger version (130K):
[in this window]
[in a new window]
|
FIG. 5. Analysis of Pitx1/Hesx1:Pitx1/TLE1 double-transgenic founder embryos. (A) Loss of anterior pituitary and morphological similarity to pituitary defects in Ames df/df mice, except when the Pitx1/Hesx1 transgene encodes a mutated eh1 domain, which cannot interact with TLE1. H&E staining. (B) In situ hybridization showing loss of growth hormone (GH), Pit-1, and ventral Prop-1, while expression of proopiomelanocortin (POMC) appears unaffected and Lhx3 and Prop-1 continue to be expressed in the ectoderm of RP. Asterisk indicates the dorsal pouch ectoderm.
|
|
However, when specific interaction between transgenically expressed TLE1 and Hesx1 was abolished through mutation of the eh1 domain, no defects occurred in the appearance of pituitary cell types, nor was organ morphology altered (Figure 5B). Thus, specific interactions between TLE1 and Hesx1 are required for Hesx1 repression in vivo; in this case, to prevent the appearance of the Pit-1 and gonadotrope lineages.
|
VI. Conclusions
|
|---|
The sequential actions of transcriptional repressors and activators and their required coregulatory machinery on overlapping sets of gene targets serve as a gene-regulatory strategy in mammalian organogenesis, exemplified here in anterior pituitary development. Two highly related paired-like homeodomain factors — Hesx1/Rpx and Prop-1 — with distinct but overlapping patterns of expression over the entire period of pituitary organogenesis (including initial commitment, patterning, and cell-type determination) exert temporally specific roles (Figure 6). Hesx1, influenced by the actions of the linked modifier genes based on the genetic background, is required for early organ commitment and cell-determination events. Hesx1, with TLE1, serves to prevent Prop-1 from initiating the program required for asymmetric division and proliferation of the Pit-1 and gonadotrope lineages. Conversely, premature expression of Prop-1 can block pituitary organogenesis, phenocopying the effects of Hesx1-gene deletion. These data suggest that the switch in binding of a paired-like homeodomain repressor for a paired-like homeodomain activator results in alteration in the expression of key target genes and prevents organogenesis. Maintained expression of Hesx1, with the TLE1 corepressor, subsequently can block the activation of Prop-1-dependent genes required for appearance of four anterior pituitary cell types. Thus, opposing actions of related repressors and activators, potentially binding to overlapping sets of gene targets, provide critical temporal control of organ development. Interestingly, later persistent expression of Prop-1 under control of the GSU promoter caused decreased gonadotrope differentiation and increased adenomatous hyperplasia (Cushman et al., 2001). This indicates that properly extinguishing Prop-1 also may be an important later step in paired-like homeodomain-mediated organogenesis.
View larger version (20K):
[in this window]
[in a new window]
|
FIG. 6. Model for the temporal switch of a homeodomain repressor for an activator, mediated by the coordinate recruitment of distinct corepressor complexes in pituitary organogenesis. Hesx1 requires the recruitment of coordinately expressed TLE1 for early repression events involved in the induction of RP and to antagonize in vivo activation by Prop-1. Downregulation of Hesx1 is required to temporally control Prop-1 function in proliferation and determination of four pituitary cell lineages.
|
|
Hesx1 appears to contain two repressor domains, located in the N-terminal and homeodomain regions of the protein, each recruiting a distinct corepressor complex. The corepressors recruited by the N-terminus includes one mammalian Groucho orthologue, TLE1, that appears to be required for Hesx1-dependent repression. In vivo, only coexpression of both Hesx1 and TLE1 are sufficient to phenocopy the effects of Prop-1 gene deletion. The strong association between TLE1 and Hesx1 is mediated by a highly conserved helical motif (FXLXXIL) present in the Hesx1 N-terminus, analogous to interactions of Nkx, Six, and certain Pax homeodomain factors with other TLE family members (Eberhard et al., 2000; Muhr et al., 2001).
The domains required for effective repression function appears to depend upon cellular and promoter context. Under specific circumstances, the Hesx1/Rpx homeodomain region is alone capable of mediating repression, utilizing a corepressor complex that includes mSin3A/B, histone deacetylases (HDACs) 1 and 2, but not of the high-affinity N-CoR/TBL1/HDAC3 complex (Guenther et al., 2000, Underhill et al., 2000) to the Hesx1 homeodomain. The Hesx1 N-terminal domain binding TLE permits cooperative binding of N-CoR/HDAC1/Sin3A/B to the homeodomain, a strategy that might be quite common with respect to many homeodomain repressors, and provides an additional linkage between TLEs and N-CoR/mSin3 complexes in the actions of strong homeodomain repressors.
Thus, coordinated regulation of a repressor (Hesx1) and corepressor (TLE1) serves as a determinant of organogenesis and the temporal control in pituitary cell lineage generation. The sequential repression and activation of a common set of regulatory genes may prove to be an underlying strategy in the temporal code of pituitary organ development, with initial repression required for organ commitment and proliferation, and subsequent activation for commitment of specific cell lineages.
|
REFERENCES
|
|---|
- Andersen B, Pearse RV II, Jenne K, Sornson M, Lin SC, Bartke A, Rosenfeld MG 1995
The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol
172
: 495
–503[CrossRef][Medline]
- Bach I, Rhodes SJ, Pearse RV II, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG 1995
P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci USA
92
: 2720
–2724[Abstract/Free Full Text]
- Bartke A 1965
The response of two types of dwarf mice to growth hormone, thyrotropin, and thyroxine. Gen Comp Endocrinol
5
: 418
–426[CrossRef][Medline]
- Buckwalter MS, Katz RW, Camper SA 1991
Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross. Genomics
10
: 515
–526[CrossRef][Medline]
- Camper SA, Saunders TL, Katz RW, Reeves RH 1990
The Pit-1 transcription factor gene is a candidate for the murine Snell dwarf mutation. Genomics
8
: 586
–590[CrossRef][Medline]
- Chen G, Courey AJ 2000
Groucho/TLE family proteins and transcriptional repression. Gene
249
: 1
–16[CrossRef][Medline]
- Cogan JD, Wu W, Phillips JA III, Arnhold IJ, Agapito A, Fofanova OV, Osorio MG, Bircan I, Moreno A, Mendonca BB 1998
The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J Clin Endocrinol Metab
83
: 3346
–3349[Abstract/Free Full Text]
- Couly G, Le Douarin NM 1988
The fate map of the cephalic neural primordium at the presomitic to the 3-somite stage in the avian embryo. Development
103
: 101
–113
- Cushman LJ, Watkins-Chow DE, Brinkmeier ML, Raetzman LT, Radak AL, Lloyd RV, Camper SA 2001
Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility. Hum Mol Genet
10
: 1141
–1153[Abstract/Free Full Text]
- Dasen JS, Rosenfeld MG 2001
Signaling and transcriptional mechanisms in pituitary development. Ann Rev Neurosci
24
: 327
–355[CrossRef][Medline]
- Dattani MT, Martinez-Barbera JP, Thomas PQ, Brickman JM, Gupta R, Martensson IL, Toresson H, Fox M, Wales JK, Hindmarsh PC, Krauss S, Beddington RS, Robinson IC 1998
Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet
19
: 125
–133[CrossRef][Medline]
- Deladoey J, Fluck C, Buyukgebiz A, Kuhlmann BV, Eble A, Hindmarsh PC, Wu W, Mullis PE 1999
"Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab
84
: 1645
–1650[Abstract/Free Full Text]
- Dietrich WF, Miller J, Steen R, Merchant MA, Damron-Boles D, Husain Z, Dredge R, Daly MJ, Ingalls KA, O’Connor TJ, et al. 1996
A comprehensive genetic map of the mouse genome. Nature
380
: 149
–152[CrossRef][Medline]
- Douglas KR, Brinkmeier ML, Kennell JA, Eswara P, Harrison TA, Patrianakos AI, Sprecher BS, Potok MA, Lyons RH Jr, MacDougald OA, Camper SA 2001
Identification of members of the Wnt signaling pathway in the embryonic pituitary gland. Mamm Genome
12
: 843
–851[CrossRef][Medline]
- Eberhard D, Jimenez G, Heavey B, Busslinger M 2000
Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. EMBO J
19
: 2292
–2303[CrossRef][Medline]
- Ericson J, Norlin S, Jessell T, Edlund T 1998
Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development
125
: 1005
–1015[Abstract]
- Fluck C, Deladoey J, Rutishauser K, Eble A, Marti U, Wu W, Mullis PE 1998
Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg
Cys at codon 120 (R120C). J Clin Endocrinol Metab
83
: 3727
–3734[Abstract/Free Full Text]
- Gage PJ, Brinkmeier ML, Scarlett LM, Knapp LT, Camper SA, Mahon KA 1996
The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. Mol Endocrinol
10
: 1570
–1581[Abstract]
- Gage PJ, Roller ML, Saunders TL, Scarlett LM, Camper SA 1996
Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion. Development
122
: 151
–160[Abstract]
- Gage PJ, Suh H, Camper SA 1999
Dosage requirement of Pitx2 for development of multiple organs. Development
126
: 4643
–4651[Abstract]
- Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE 1993
GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet
4
: 227
–232[CrossRef][Medline]
- Gromoller A, Lehming N 2000
Srb7p is a physical and physiological target of Tup1p. EMBO J
19
: 6845
–6852[CrossRef][Medline]
- Guenther MG, Lane WS, Fischle W, Verdin E, Lazar MA, Shiekhattar R 2000
A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev
14
: 1048
–1057[Abstract/Free Full Text]
- Hermesz E, Mackem S, Mahon KA 1996
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
122
: 41
–52[Abstract]
- Jimenez G, Paroush Z, Ish-Horowicz D 1997
Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev
11
: 3072
–3082[Abstract/Free Full Text]
- Kuchin S, Carlson M 1998
Functional relationships of Srb10-Srb11 kinase, carboxy-terminal domain kinase CTDK-I, and transcriptional corepressor Ssn6-Tup1. Mol Cell Biol
18
: 1163
–1171[Abstract/Free Full Text]
- Laherty CD, Billin AN, Lavinsky RM, Yochum GS, Bush AC, Sun JM, Mullen TM, Davie JR, Rose DW, Glass CK, Rosenfeld MG, Ayer DE, Eisenman RN 1998
SAP30, a component of the mSin3 corepressor complex involved in N-CoR-mediated repression by specific transcription factors. Mol Cell
2
: 33
–42[CrossRef][Medline]
- Lamonerie T, Tremblay JJ, Lanctot C, Therrien M, Gauthier Y, Drouin J 1996
Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev
10
: 1284
–1295[Abstract/Free Full Text]
- Li S, Crenshaw EB III, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG 1990
Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature
347
: 528
–533[CrossRef][Medline]
- Li S-C, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG 1993
Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature
364
: 208
–213[CrossRef][Medline]
- Lin CR, Kioussi C, O’Connell S, Briata P, Szeto D, Liu F, Izpisua-Belmonte JC, Rosenfeld MG 1999
Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature
401
: 279
–282[CrossRef][Medline]
- Lisitsyn N, Lisitsyn N, Wigler M 1993
Cloning the differences between two complex genomes. Science
259
: 946
–951[Abstract]
- Lisitsyn NA, Segre JA, Kusumi K, Lisitsyn NM, Nadeau JH, Frankel WN, Wigler MH, Lander ES 1994
Direct isolation of polymorphic markers linked to a trait by genetically directed representational difference analysis. Nat Genet
6
: 57
–63[CrossRef][Medline]
- Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF 1999
Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature
401
: 276
–278[CrossRef][Medline]
- Martinez-Barbera JP, Rodriguez TA, Beddington RS 2000
The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Dev Biol
223
: 422
–430[CrossRef][Medline]
- Muhr J, Andersson E, Persson M, Jessell TM, Ericson J 2001
Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube. Cell
104
: 861
–873[CrossRef][Medline]
- Paroush Z, Finley RL Jr, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D 1994
Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Cell
79
: 805
–815[CrossRef][Medline]
- Pernasetti F, Toledo SP, Vasilyev VV, Hayashida CY, Cogan JD, Ferrari C, Lourenco DM, Mellon PL 2000
Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301–302delAG) in the prophet of Pit-1 gene. J Clin Endocrinol Metab
85
: 390
–397[Abstract/Free Full Text]
- Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin SC, Yu VC, Rosenfeld MG 1993
A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev
7
: 913
–932[Abstract/Free Full Text]
- Seidah NG, Barale JC, Marcinkiewicz M, Mattei MG, Day R, Chretien M 1994
The mouse homeoprotein mLIM-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary. DNA Cell Biol
13
: 1163
–1180[Medline]
- Sheng HZ, Moriyama K, Yamashita T, Li H, Potter SS, Mahon KA, Westphal H 1997
Multistep control of pituitary organogenesis. Science
278
: 1809
–1812[Abstract/Free Full Text]
- Sheng HZ, Westphal H 1999
Early steps in pituitary organogenesis. Trends Genet
15
: 236
–240[CrossRef][Medline]
- Sheng HZ, Zhadanov AB, Mosingerm B Jr, Fujii T, Bertuzzi S, Grinberg A, Lee EJ, Huang SP, Mahon KA, Westphal H 1996
Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science
272
: 1004
–1007[Abstract]
- Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, Swanson LW 1990
Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev
4
: 693
–711
- Smith ST, Jaynes JB 1996
A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development
122
: 3141
–3150[Abstract]
- Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O’Connell SM, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG 1996
Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature
384
: 327
–333[CrossRef][Medline]
- Szeto DP, Ryan AK, O’Connell SM, Rosenfeld MG 1996
P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc Natl Acad Sci USA
93
: 7706
–7710[Abstract/Free Full Text]
- Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M, Cameron F, Hurst J, Woods K, Dunger D, Stanhope R, Forrest S, Robinson IC, Beddington RS 2001
Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet
10
: 39
–45[Abstract/Free Full Text]
- Tolkunova EN, Fujioka M, Kobayashi M, Deka D, Jaynes JB 1998
Two distinct types of repression domain in engrailed: one interacts with the groucho corepressor and is preferentially active on integrated target genes. Mol Cell Biol
18
: 2804
–2814[Abstract/Free Full Text]
- Treier M, O’Connell S, Gleiberman A, Price J, Szeto DP, Burgess R, Chuang PT, McMahon AP, Rosenfeld MG 2001
Hedgehog signaling is required for pituitary gland development. Development
128
: 377
–386[Abstract]
- Treier M, Gleiberman AS, O’Connell SM, Szeto DP, McMahon JA, McMahon AP, Rosenfeld MG 1998
Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev
12
: 1691
–1704[Abstract/Free Full Text]
- Underhill C, Qutob MS, Yee SP, Torchia J 2000
A novel nuclear receptor corepressor complex, N-CoR, contains components of the mammalian SWI/SNF complex and the corepressor KAP-1. J Biol Chem
275
: 40463
–40470[Abstract/Free Full Text]
- Voss JW, Rosenfeld MG 1992
Anterior pituitary development: short tales from dwarf mice. Cell
70
: 527
–530[CrossRef][Medline]
- Watanabe YG 1982
An organ culture study on the site of determination of ACTH and LH cells in the rat adenohypophysis. Cell Tiss Res
227
: 257
–266[CrossRef][Medline]
- Watson AD, Edmondson DG, Bone JR, Mukai Y, Yu Y, Du W, Stillman DJ, Roth SY 2000
Ssn6-Tup1 interacts with class I histone deacetylases required for repression. Genes Dev
14
: 2737
–2744[Abstract/Free Full Text]
- Wilson D, Sheng G, Lecuit T, Dostatni N, Desplan C 1993
Cooperative dimerization of paired class homeo domains on DNA. Genes Dev
7
: 2120
–2134[Abstract/Free Full Text]
- Wu J, Suka N, Carlson M, Grunstein M 2001
TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. Mol Cell
7
: 117
–126[CrossRef][Medline]
- Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O’Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA III, Rosenfeld MG 1998
Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet
18
: 147
–149[CrossRef][Medline]
- Xu L, Lavinsky RM, Dasen JS, Flynn SE, McInerney EM, Mullen TM, Heinzel T, Szeto D, Korzus E, Kurokawa R, Aggarwal AK, Rose DW, Glass CK, Rosenfeld MG 1998
Signal-specific co-activator domain requirements for Pit-1 activation. Nature
395
: 301
–306[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
D. Kelberman, S. C. P. de Castro, S. Huang, J. A. Crolla, R. Palmer, J. W. Gregory, D. Taylor, L. Cavallo, M. F. Faienza, R. Fischetto, et al.
SOX2 Plays a Critical Role in the Pituitary, Forebrain, and Eye during Human Embryonic Development
J. Clin. Endocrinol. Metab.,
May 1, 2008;
93(5):
1865 - 1873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. G. Oliver, T. A. Read, J. D. Kessler, A. Mehmeti, J. F. Wells, T. T. T. Huynh, S. M. Lin, and R. J. Wechsler-Reya
Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma
Development,
May 15, 2005;
132(10):
2425 - 2439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Reynaud, M. Chadli-Chaieb, S. Vallette-Kasic, A. Barlier, J. Sarles, I. Pellegrini-Bouiller, A. Enjalbert, L. Chaieb, and T. Brue
A Familial Form of Congenital Hypopituitarism Due to a PROP1 Mutation in a Large Kindred: Phenotypic and in Vitro Functional Studies
J. Clin. Endocrinol. Metab.,
November 1, 2004;
89(11):
5779 - 5786.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
I. Prophet of Pit-1 (Prop-1)
