Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

Flavell, David M.; Wells, Timothy; Wells, Sara; Carmignac, Danielle; Thomas, Graham H.; Robinson, I. C. A. F.

doi:10.1002/j.1460-2075.1996.tb00761.x

Cited by 78 publications

(43 citation statements)

References 67 publications

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“…Parlow (National Hormone & Peptide Program, Torrance, California, USA). For growth hormone immunohistochemistry, we used a 1:2,000 dilution of a monkey antibody to rat growth hormone serum from the NHPP as previously described 39 .…”

Section: Methodsmentioning

confidence: 99%

SOX3 is required during the formation of the hypothalamo-pituitary axis

Rizzoti¹,

Brunelli²,

Carmignac³

et al. 2004

Nat Genet

274

271

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The development of complex organs composed of different cell types frequently depends on reciprocal induction events occurring between distinct tissue layers that lie adjacent to one another in the embryo. The pituitary is a well studied case in point. It originates from two ectoderm-derived tissues, with the posterior lobe developing from an evagination of the ventral diencephalon, the infundibulum, and the intermediate and anterior lobes deriving from Rathke's pouch, an invaginating domain in the roof of the oral ectoderm 1 . In the mature gland, the posterior lobe contains axon terminal projections from two populations of hypothalamic neuroendocrine neurons. The anterior and intermediate lobes contain several different endocrine cell types whose proliferation, hormone synthesis and secretion are regulated by factors secreted from hypothalamic neuroendocrine neurons.During early development the infundibulum has an inductive role in the formation of the pituitary. For example, the genetic ablation of this domain in Titf1-null mice results in the complete absence of the pituitary gland 2 . The essential signaling molecules made by the infundibulum are thought to be FGF8 and BMP4, as both are necessary to induce early development of Rathke's pouch. FGF and BMP signals are also required to control the pattern of differentiation of cell types derived from Rathke's pouch 3,4 .Even subtle mutations that affect signaling pathways during early organogenesis can have profound effects on subsequent development and specification of mature cell types. These could arise in genes encoding the signaling molecules or their receptors, in transcription factors responsible for their expression or in genes required to specify the interacting tissues. In humans, SOX3, an HMG box protein (for review see ref. 5), is implicated in a syndrome of X-linked hypopituitarism and mental retardation 6 . In a single family whose males were deficient in growth hormone, a mutation in SOX3 was identified. The consequences of this mutation on the function of the protein are not known. X-chromosome deletions encompassing SOX3 are linked to several syndromes in humans, including mental retardation, but defects in pituitary function have not been reported 7,8 .SOX3 is a single-exon gene on the X chromosome in all mammals and is thought to be the gene from which SRY, the Y-linked testis determining gene, evolved 9,10 . Based on sequence homology, however, SOX3 is more closely related to SOX1 and SOX2 (refs. 5,11). Together they comprise the SOXB1 subfamily and are coexpressed throughout the developing CNS [11][12][13] . To study the role of Sox3, we targeted null mutations in the gene into XY embryonic stem (ES) cells, but injection of these cells into blastocysts resulted in early lethality of the chimeras due to a gastrulation defect (M. Parsons, C. Wise, S.B., M. CohenTannoudji, K.R., L. Pevny & R.L.-B., unpublished data).Therefore, to access later functions of SOX3, we initiated experiments using a conditional targeting strategy. In contrast to th...

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Section: Methodsmentioning

confidence: 99%

SOX3 is required during the formation of the hypothalamo-pituitary axis

Rizzoti¹,

Brunelli²,

Carmignac³

et al. 2004

Nat Genet

274

271

View full text Add to dashboard Cite

show abstract

“…Parlow (Torrance, California, USA). For GH immunohistochemistry, a 1:2,000 dilution of a monkey anti-rat GH serum from the NHPP was used as previously described (51). The same protocol was used with a 1:500 dilution of the rabbit anti-rat βLH serum from the NHPP.…”

Section: Murine Analysismentioning

confidence: 99%

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans

Kelberman

Rizzoti

Avilion

et al. 2006

Journal of Clinical Investigation

208

293

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The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice. Introduction SOX2 is a member of the sex-determining region of the Y chromosome-related (SRY-related) high-mobility group (HMG) box (SOX) family of transcription factors, encoded by 20 genes in humans and mice, each of which carries a 79-amino acid HMG box DNA-binding domain similar to that of SRY as well as domains implicated in transcriptional regulation (1, 2). Based on HMG box homology, they are grouped into different subfamilies. SOX1, SOX2, and SOX3 belong to the B1 subfamily and are expressed in various phases of embryonic development and cell differentiation, where they play critical roles in embryogenesis (3, 4). All 3 mark neuroepithelial progenitors and stem cells from the earliest stages of development, and there is a strong, but not absolute, tendency for them to be downregulated as cells differentiate.In the mouse, Sox2 RNA is first detected in cells at the morula stage (2.5 dpc) and then in the inner cell mass of the blastocyst (3.5 dpc).

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“…In the Tgr model, the expression of human GH (hGH) in the GH-releasing hormone neurons leads to a 70 -90% reduction in pituitary GH (13,17) …”

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confidence: 99%

“…We have investigated the development of visceral and bone marrow adiposity in dw/dw rats and compared the developing adiposity profile with that in the moderately GH-deficient transgenic growth retarded (Tgr) rat (17). In the Tgr model, the expression of human GH (hGH) in the GH-releasing hormone neurons leads to a 70 -90% reduction in pituitary GH (13,17) and a 70% reduction in the amplitude of spontaneous GH pulses (17,36).…”

mentioning

confidence: 99%

Adiposity profile in the dwarf rat: an unusually lean model of profound growth hormone deficiency

Davies

Gevers²,

Stevenson³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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This study describes the previously uncharacterized ontogeny and regulation of truncal adipose reserves in the profoundly GH-deficient dwarf (dw/dw) rat. We show that, despite normal proportionate food intake, dw/dw rats develop abdominal leanness and hypoleptinemia (circulating leptin halved in dw/dw males, P Ͻ 0.05) during puberty. This contrasts with the hyperleptinemia seen in moderately GH-deficient Tgr rats (circulating leptin doubled at 6 wk of age, P Ͻ 0.05) and in GH receptor-binding protein (GHR/BP)-null mice (circulating leptin doubled; P Ͻ 0.05). This lean/hypoleptinemic phenotype was not completely normalized by GH treatment, but dw/dw rats developed abdominal obesity in response to neonatal MSG treatment or maintenance on a high-fat diet. Unlike Tgr rats, dw/dw rats did not become obese with age; plasma leptin levels and fat pad weights became similar to those in wild-type rats. In contrast with truncal leanness, tibial marrow adiposity was normal in male and doubled in female dwarves (P Ͻ 0.01), this increase being attributable to increased adipocyte number (P Ͻ 0.01). Neonatal MSG treatment and high-fat feeding elevated marrow adiposity in dw/dw rats by inducing adipocyte enlargement (P Ͻ 0.05). These results demonstrate that, despite lipolytic influence of GH, severe GH deficiency in dw/dw rats is accompanied by a paradoxical leanness. This lean/hypoleptinemic phenotype is not solely attributable to reduced GH signaling and does not appear to result from a reduction in nutrient intake or the ability of dw/dw adipocytes to accumulate lipid. Disruption of preadipocyte differentiation or adipocyte proliferation in the dw/dw rat may lead to the development of this unusually lean/hypoleptinemic phenotype. adipose tissue; bone marrow fat; leptin; dwarfism IT IS WELL ESTABLISHED that growth hormone (GH) deficiency is usually accompanied by an increase in fat accumulation, whereas conditions of GH excess are normally associated with leanness. However, recent studies have revealed that the relationship between GH status and the degree of adiposity is far from simple. For example, although it is assumed that obesity results from the removal of the lipolytic influence of GH (37), it is also recognized that abdominal obesity results in a secondary reduction in GH secretion (35). Similarly, whereas GH replacement in patients with primary GH deficiency leads to specific depletion of intra-abdominal fat (2, 12), the administration of GH to treat obesity in GH-replete individuals does not elicit a consistent reduction or redistribution in body fat (31). Some of these apparent contradictions may be explained by the depot-specific sensitivity of adipose tissue to the lipolytic action of GH (19). The relationship between GH status and adiposity in rodent models of GH deficiency is similarly complex. In the profoundly GH-deficient lit/lit mouse a significant elevation in total proportionate fat mass (14) is reflected in increased inguinal and retroperitoneal fat, whereas parametrial fat is unaffected (26). In addit...

show abstract

Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

Cited by 78 publications

References 67 publications

SOX3 is required during the formation of the hypothalamo-pituitary axis

SOX3 is required during the formation of the hypothalamo-pituitary axis

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans

Adiposity profile in the dwarf rat: an unusually lean model of profound growth hormone deficiency

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