Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis

Autor: Leah B. Goldberg, Lori T. Raetzman, Paven K. Aujla
Rok vydání: 2011
Předmět:
medicine.medical_specialty
Hypothalamo-Hypophyseal System
Notch
Pro-Opiomelanocortin
Cellular differentiation
Melanotrophs
SOX2
Notch signaling pathway
Pituitary-Adrenal System
Biology
Article
03 medical and health sciences
Mice
Melanotrope
Internal medicine
medicine
Animals
Transcription factor
Molecular Biology
Corticotrophs
Corticotrope
030304 developmental biology
DNA Primers
0303 health sciences
Receptors
Notch
Reverse Transcriptase Polymerase Chain Reaction
HPA axis
SOXB1 Transcription Factors
030302 biochemistry & molecular biology
Gene Expression Regulation
Developmental
Cell Differentiation
Cell Biology
Immunohistochemistry
Endocrinology
Pituitary
Hes3 signaling axis
Corticotropic cell
Signal transduction
Corticosterone
Developmental Biology
Signal Transduction
Transcription Factors
Zdroj: Developmental biology. 358(1)
ISSN: 1095-564X
Popis: The hypothalamic-pituitary-adrenal (HPA) axis is an important regulator of energy balance, immune function and the body's response to stress. Signaling networks governing the initial specification of corticotropes, a major component of this axis, are not fully understood. Loss of function studies indicate that Notch signaling may be necessary to repress premature differentiation of corticotropes and to promote proliferation of pituitary progenitors. To elucidate whether Notch signaling must be suppressed in order for corticotrope differentiation to proceed and whether Notch signaling is sufficient to promote corticotrope proliferation, we examined the effects of persistent Notch expression in Pomc lineage cells. We show that constitutive activation of the Notch cascade inhibits the differentiation of both corticotropes and melanotropes and results in the suppression of transcription factors required for Pomc expression. Furthermore, persistent Notch signaling traps cells in the intermediate lobe of the pituitary in a progenitor state, but has no effect on pituitary proliferation. Undifferentiated cells are eliminated in the first two postnatal weeks in these mice, resulting in a modest increase in CRH expression in the paraventricular nucleus, hypoplastic adrenal glands and decreased stress-induced corticosterone levels. Taken together, these findings show that Notch signaling is sufficient to prevent corticotrope and melanotrope differentiation, resulting in dysregulation of the HPA axis.
Databáze: OpenAIRE
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