Distal modular enhancer complex acts to control pituitary-and nervous system-specific expression of the LHX3 regulatory gene

Rachel D. Mullen, Soyoung Park, Simon Rhodes

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Lin-11, Isl-1, and Mec-3 (LIM)-homeodomain (HD)-class transcription factors are critical for many aspects of mammalian organogenesis. Of these, LHX3 is essential for pituitary gland and nervous system development. Pediatric patients with mutations in coding regions of the LHX3 gene have complex syndromes, including combined pituitary hormone deficiency and nervous system defects resulting in symptoms such as dwarfism, thyroid insufficiency, infertility, and developmental delay. The pathways underlying early pituitary development are poorly understood, and the mechanisms by which the LHX3 gene is regulated in vivo are not known. Using bioinformatic and transgenic mouse approaches, we show that multiple conserved enhancers downstream of the human LHX3 gene direct expression to the developing pituitary and spinal cord in a pattern consistent with endogenous LHX3 expression. Several transferable cis elements can individually guide nervous system expression. However, a single 180-bp minimal enhancer is sufficient to confer specific expression in the developing pituitary. Within this sequence, tandem binding sites recognized by the islet-1 (ISL1) LIM-HD protein are essential for enhancer activity in the pituitary and spine, and a pituitary homeobox 1 (PITX1) bicoid class HD element is required for spatial patterning in the developing pituitary. This study establishes ISL1 as a novel transcriptional regulator of LHX3 and describes a potential mechanism for regulation by PITX1. Moreover, these studies suggest models for analyses of the transcriptional pathways coordinating the expression of other LIM-HD genes and provide tools for the molecular analysis and genetic counseling of pediatric patients with combined pituitary hormone deficiency.

Original languageEnglish
Pages (from-to)308-319
Number of pages12
JournalMolecular Endocrinology
Volume26
Issue number2
DOIs
StatePublished - Feb 1 2012

Fingerprint

Regulator Genes
Nervous System
Homeobox Genes
LIM-Homeodomain Proteins
Pediatrics
Genes
Dwarfism
Organogenesis
Genetic Counseling
Pituitary Gland
Computational Biology
Infertility
Transgenic Mice
Molecular Biology
Spinal Cord
Thyroid Gland
Spine
Transcription Factors
Binding Sites
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Distal modular enhancer complex acts to control pituitary-and nervous system-specific expression of the LHX3 regulatory gene. / Mullen, Rachel D.; Park, Soyoung; Rhodes, Simon.

In: Molecular Endocrinology, Vol. 26, No. 2, 01.02.2012, p. 308-319.

Research output: Contribution to journalArticle

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