Lack of the murine homeobox gene<i>Hesx1</i>leads to a posterior transformation of the anterior forebrain

Andoniadou, Cynthia L.; Signore, Massimo; Sajedi, Ezat; Gaston‐Massuet, Carles; Kelberman, Daniel; Burns, Alan J.; Itasaki, Nobue; Dattani, Mehul; Martinez-Barbera, Juan Pedro

doi:10.1242/dev.02829

Cited by 80 publications

(137 citation statements)

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“…The forebrain and pituitary defects observed in the Hesx1 Cre/+ ;Tcf7l1 flox/− mutants are very similar to those previously described in Hesx1-deficient embryos, suggesting that these transcriptional repressors may control the same genetic program (49,54). Because mutations in HESX1 have been associated with congenital hypopituitarism in humans, including SOD (60, 61), we hypothesized that mutations in TCF7L1 may also be implicated in these conditions.…”

Section: Variants In Tcf7l1 Are Associated With Forebrain and Pituitarysupporting

confidence: 56%

“…The Hesx1 Cre/+ (49), Tcf7l1 flox/flox (44), and Tcf7l1 ΔN/ΔN (33) have been previously described. We have previously shown that the Hesx1-Cre mouse line drives efficient recombination of loxP-flanked DNA in RP progenitors from 9.5 dpc (49,50). Hesx1 Cre/+ ;R26 loxP-YFP/+ 18.5 dpc embryos display widespread yellow fluorescent protein (YFP) expression in the vast majority of cells of the anterior pituitary, suggesting that the Hesx1-expressing RP progenitors give rise to all hormone-producing cells (Hesx1-cell lineage).…”

Section: Methodsmentioning

confidence: 99%

“…Hesx1 Cre/+ ;R26 loxP-YFP/+ 18.5 dpc embryos display widespread yellow fluorescent protein (YFP) expression in the vast majority of cells of the anterior pituitary, suggesting that the Hesx1-expressing RP progenitors give rise to all hormone-producing cells (Hesx1-cell lineage). In addition to RP, Hesx1 Cre/+ ;R26 loxP-YFP/+ and Hesx1 Cre/+ ;R26 loxP-lacZ/+ embryos show reporter expression in the ventral telencephalon and preoptic hypothalamic area from 9.5 dpc (49)(50)(51). Tcf7l1 is expressed in the forebrain, including the hypothalamic area, as well as in the anterior pituitary until 14.5 dpc (37).…”

Section: Methodsmentioning

confidence: 99%

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Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

Gaston‐Massuet

McCabe

Scagliotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/β-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamopituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with β-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.WNT pathway | pituitary | Tcf7l1 | septooptic dysplasia | hypopituitarism

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Section: Variants In Tcf7l1 Are Associated With Forebrain and Pituitarysupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

Gaston‐Massuet

McCabe

Scagliotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the HRP-labelled embryos are too young to show any morphological evidence of Rathke's pouch, it is likely, given the results obtained in other animal models, that some precursors of the VEAP are founders of the anterior pituitary primordium. This hypothesis is strongly supported by the genetic fate map of Hesx1-expressing cells in the normal mouse embryo (Andoniadou et al, 2007).…”

Section: Anr Origin and Derivatives In Mouse And Other Vertebratesmentioning

confidence: 79%

Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

et al. 2012

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SUMMARYIn the mouse embryo the anterior ectoderm undergoes extensive growth and morphogenesis to form the forebrain and cephalic non-neural ectoderm. We traced descendants of single ectoderm cells to study cell fate choice and cell behaviour at late gastrulation. In addition, we provide a comprehensive spatiotemporal atlas of anterior gene expression at stages crucial for anterior ectoderm regionalisation and neural plate formation. Our results show that, at late gastrulation stage, expression patterns of anterior ectoderm genes overlap significantly and correlate with areas of distinct prospective fates but do not define lineages. The fate map delineates a rostral limit to forebrain contribution. However, no early subdivision of the presumptive forebrain territory can be detected. Lineage analysis at single-cell resolution revealed that precursors of the anterior neural ridge (ANR), a signalling centre involved in forebrain development and patterning, are clonally related to neural ectoderm. The prospective ANR and the forebrain neuroectoderm arise from cells scattered within the same broad area of anterior ectoderm. This study establishes that although the segregation between non-neural and neural precursors in the anterior midline ectoderm is not complete at late gastrulation stage, this tissue already harbours elements of regionalisation that prefigure the later organisation of the head.

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“…Within the pouch, this results in the induction of a cascade of transcription factors that are involved in patterning and terminal cell differentiation. Some (Six3, Pax6, Hesx1) are already expressed within the pituitary primordium and continue to be expressed in Rathke's pouch (Dasen & Rosenfeld 2001, Andoniadou et al 2007, Zhu et al 2007b. Concurrent with organ commitment, LIM-homeodomain factors (Lhx3 and Lhx4) and OTXrelated factors (Ptx1/P-OTX) are also expressed in the pouch.…”

Section: Overview Of Normal Pituitary Developmentmentioning

confidence: 99%

The role of SOX proteins in normal pituitary development

Alatzoglou¹,

Kelberman²,

Dattani³

2008

Journal of Endocrinology

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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.

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Lack of the murine homeobox geneHesx1leads to a posterior transformation of the anterior forebrain

Cited by 80 publications

References 62 publications

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans

Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

The role of SOX proteins in normal pituitary development

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