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BDNF engages pituitary stem cells for establishment of the adult gland and for homeostasis of the corticotrope lineage

ABSTRACT: The development and maintenance of complex organs rely on the balanced expansion of cells of different lineages to establish a functional tissue. In the pituitary gland, maintenance of the adult corticotrope lineage relies heavily on replication of differentiated cells. In contrast in pathological conditions, such as adrenalectomy that depletes circulating glucocorticoids (Gc), pituitary stem cells (PSC) are activated to increase the number of corticotropes. In the present work, we used the proopiomelanocortin (POMC) knockout mouse model of Gc deficiency to characterize pre-corticotrope precursors that are normally rare and short lived but accumulate in this model. Differentiation of PSCs into pre-corticotropes is repressed by Gc and requires the lineage-specific transcription factor Tpit. Pre-corticotrope maintenance is dependent on a brain-derived neurotropic factor (BDNF) autocrine loop that is sensitive to Gc. In normal development, BDNF is critical for engagement of PSCs into proliferation and differentiation during the postnatal expansion of the gland.

ORGANISM(S): Mus musculus

PROVIDER: GSE316726 | GEO | 2026/01/20

REPOSITORIES: GEO

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Project description:While the hypothalamo-pituitary-adrenal axis (HPA) activates a general stress response by increasing glucocorticoid (Gc) synthesis, biological stress resulting from infections triggers the inflammatory response through production of cytokines. The pituitary gland integrates some of these signals by responding to the pro-inflammatory cytokines IL6 and LIF and to a negative Gc feedback loop. The present work used whole-genome approaches to define the LIF/STAT3 regulatory network and to delineate cross-talk between this pathway and Gc action. Genome-wide ChIP-chip identified 3 449 STAT3 binding sites, whereas 2 396 genes regulated by LIF and/or Gc were found by expression profiling. Surprisingly, LIF on its own changed expression of only 85 genes but the joint action of LIF and Gc potentiated the expression of more than a thousand genes. Accordingly, activation of both LIF and Gc pathways also potentiated STAT3 and GR recruitment to many STAT3 targets. Our analyses revealed an unexpected gene cluster that requires both stimuli for delayed activation: 83% of the genes in this cluster are involved in different cell defense mechanisms. Thus, stressors that trigger both general stress and inflammatory responses lead to activation of a stereotypic innate cellular defense response. Experiment Overall Design: 1) Pituitary corticotrophs cell line (AtT-20) response to glucocorticoids and LIF: Experiment Overall Design: AtT-20 cells mRNA extracted after treatment with PBS as control, LIF for 18h, Dex+LIF for 3h and Dex+LIF for 18h. Each treatment were made in duplicate. [GSM471246-GSM471253] Experiment Overall Design: 2) Pituitary corticotrophs cell line (AtT-20) response to LIF after 3h treatment: Experiment Overall Design: AtT-20 cells mRNA extracted after treatment with PBS as control or LIF for 3h. Each treatment were made in duplicate. [GSM471254-GSM471257] Experiment Overall Design: 3) Pituitary corticotrophs cell line (AtT-20) response to Dex after 3h treatment: Experiment Overall Design: AtT-20 cells mRNA extracted after treatment with PBS as control or Dex for 3h. Each treatment were made in duplicate. [GSM471258-GSM471261] Experiment Overall Design: 4) Pituitary corticotrophs cell line (AtT-20) response to Dex after 18h treatment: Experiment Overall Design: AtT-20 cells mRNA extracted after treatment with PBS as control or Dex for 18h. Each treatment were made in duplicate. [GSM471262-GSM471269]

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BDNF engages pituitary stem cells for establishment of the adult gland and for homeostasis of the corticotrope lineage

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