Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse

@article{Dattani1998MutationsIT,
  title={Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse},
  author={Mehul Tulsidas Dattani and Juan Pedro Martinez-Barbera and Paul Q. Thomas and Joshua Mark Brickman and Raj Gupta and Inga-Lill M{\aa}rtensson and H{\aa}kan Toresson and Margaret F. Fox and Jerry K. H. Wales and Peter C. Hindmarsh and Stefan Krauss and Rosa S. P. Beddington and Iain C.A.F. Robinson},
  journal={Nature Genetics},
  year={1998},
  volume={19},
  pages={125-133}
}
During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal… 

HESX1: a novel gene implicated in a familial form of septo‐optic dysplasia

A vital role for Hesxl/HESXl in forebrain and pituitary development in mice and humans is suggested and two siblings with septo‐optic dysplasia were homozygous for a missense mutation within the HESxl.

Septo-Optic Dysplasia: From Mouse to Man

A vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man is indicated, suggesting an autosomal dominant inheritance with variable penetrance.

A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction.

A novel homozygous nonconservative missense mutation (I26T) in the critical Engrailed homology repressor domain (eh1) of HESX1 is identified, the first, to the authors' knowledge, to be described in humans, in a girl with evolving combined pituitary hormone deficiency born to consanguineous parents.

The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation.

The requirement of Hesx1 in the AVE, AME, and ANE is investigated using chimeric and in situ hybridization analyses to understand better the nature of the forebrain defects.

Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain

It is demonstrated that the absence of Hesx1 leads to a posterior transformation of the anterior forebrain (AFB) during mouse development, and the mechanism underlying this transformation is the ectopic activation of Wnt/β-catenin signalling within the HesX1 expression domain in the AFB.

Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders.

It is shown that Hesx1 is a promoter-specific transcriptional repressor with a minimal 36 amino acid repression domain which can mediate promoter- specific repression by suppressing the activity of homeodomain-containing activator proteins.

Molecular Genetics of Septo-Optic Dysplasia

A vital role for Hesx1/HESX1 in forebrain and pituitary development in mouse and man is indicated, and hence in some cases of SOD.

Deletion of OTX2 in neural ectoderm delays anterior pituitary development.

It is demonstrated that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitsary growth.

SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.

SOX2 expression patterns in human embryonic development support a direct involvement of the protein during development of tissues affected in these individuals, and suggest that a failure to repress the Wnt-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with loss-of-function mutations in SOX2.
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References

SHOWING 1-10 OF 59 REFERENCES

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

A new murine homeobox gene, Rpx, that is dynamically expressed in the prospective cephalic region of the embryo during gastrulation is isolated, suggestive of a role in the early determination or differentiation of the pituitary.

Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification.

Results demonstrate that Otx2 is first required in the visceral endoderm for the induction, and subsequently in the neuroectodermfor the specification of forebrain and midbrain territories.

The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation.

The results establish the time of df action in a cascade of genes that regulate pituitary ontogeny and demonstrate that df acts earlier in the differentiation pathway than Pit1.

Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development.

The isolation of a sequence-related gene referred to as Six3 is reported, which is one of the most anterior homeobox gene reported to date and supports the idea that mammals and insects share control genes such as eyeless/Pax6 and also possibly other members of the regulatory cascade required for eye morphogenesis.

Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome

The human cDNA and genomic characterization of a new homeobox gene, RIEG, causing Rieger syndrome is reported, providing opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis.

Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues

The expression pattern of Lhx3 is well conserved between Xenopus and mouse, underscoring the functional importance of this gene as a regulator of development.

Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly

The presence of different mutations in cases of severe schizencephaly suggests a requirement of the EMX2 protein for the correct formation of the human cerebral cortex.

Sequence, Genomic Organization, and Expression of the Novel Homeobox Gene Hesx1(*)

Hex1 expression was down-regulated during embryonic stem cell differentiation and was detected in tissue-specific RNA samples derived from the embryonic liver, and at lower levels in viscera, amnion, and yolk sac, consistent with a role for Hesx1 in the regulation of developmental decisions in the early mouse embryo and during fetal hematopoiesis.

Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse.

It is concluded that expression of GATA-4 in endoderm rather than cardiogenic mesoderm is required for ventral morphogenesis.
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