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Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo.

Abstract
The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable.
AuthorsStephanie C Colvin, Raleigh E Malik, Aaron D Showalter, Kyle W Sloop, Simon J Rhodes
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 1 Pg. 173-8 (Jan 4 2011) ISSN: 1091-6490 [Electronic] United States
PMID21149718 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Codon, Nonsense
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Lhx3 protein
  • Pituitary Hormones
  • Transcription Factors
Topics
  • Animals
  • Blotting, Western
  • Codon, Nonsense (genetics)
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Histological Techniques
  • Homeodomain Proteins (genetics, metabolism)
  • Humans
  • Hypopituitarism (etiology)
  • Immunohistochemistry
  • LIM-Homeodomain Proteins
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Pituitary Hormones (deficiency)
  • Polymerase Chain Reaction
  • Transcription Factors

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