SAT-111 - Corticotroph Genomic Remodeling with Chronic Loss of Adrenal Glucocorticoid Feedback

Introduction: Glucocorticoid (GC) deficiency after bilateral adrenalectomy (ADX) rapidly activates corticotroph via CRH/CRHR1/Gαs/cAMP/PKA/CREB and AVP/V1bR/Gαq/11/PLC/Ca²⁺ signaling, driving POMC and ACTH production. With sustained adrenal GC deficiency, as CRHR1 signaling is downregulated , maintenance of corticotroph function is proposed to shift toward AVP–V1bR–MAPK to maintain ACTH production.

Methods: We analyzed single-nucleus (sn) multiome of murine pituitaries after bilateral ADX compared to sham. Pituitaries were collected at 3 wk or 4 mo (n=3/group/time point) for snRNA-seq and snATAC-seq. Differentially expressed genes (DEs, adjP < 0.05) and differential heterochromatin peaks (DPs, adjP < 0.05) were identified using standard pipelines (Scanpy and ArchR). Corticosterone and ACTH levels were measured by ELISA.

Results: In ADX mice, ACTH increased and corticosterone decreased vs sham, confirming loss of GC negative feedback. Amongst all the pituitary cell types, corticotrophs showed the strongest response (415 up DEs at 3 wk; 579 at 4 mo). KEGG (adjP < 0.05) identified 15 pathways at 3 wk (14 G-protein-associated: Gαs n=5, Gαq/11 n=6, Gαi n=3) and 50 at 4mo (31 G-protein–associated: Gαs n=13, Gαq/11 n=11, Gαi n=7). Canonical CRH/AVP genes with concordant DE+DP showed time-dependent remodeling of POMC production.

After 3wks: Crhr1 and Avpr1b were unchanged, and proximal effectors reduced (Adcy2 x0.85, Plcb1 x0.45) .PDE buffering increased (Pde4b x4.43, Pde4d x1.91, Pde3b x1.86, Pde10a x2.22, Pde1c x3.49; Pde1a x0.64). High output persisted for Pomc (x3.82) with Ca2+ remodeling (Itpr2 x2.03, Cacna1a x1.64, Calm2 x1.34, Atp2b1 x1.62, Atp2b2 x1.50, Slc8a1 x1.43, Camk4 x3.59) and MAPK/trafficking (Ptk2b x1.39, Vav3 x7.2, Rap1a x2.25, Tiam1 x1.24, Map2k1 x1.31, Mapk9 x1.81, Creb3l2 x2.15).

After 4 mo: Crhr1 and Avpr1b were reduced (x0.51 and x0.15 respectively ) and 2nd messengers attenuated (Adcy2 x0.36, Adcy3 x0.43, Adcy5 x0.36; Plcb1 x0.76, Plcd1 x0.77, Plce1 x0.31) with stronger PDE buffering (Pde4b x5.91, Pde4d x1.58, Pde3b x1.51, Pde10a x2.62, Pde1c x5.16). Pomc was markedly induced (x6.35) with Ca2+/excitability and remodeling (Ryr3 x5.48, Cacna1a x3.69, Cacna1b x1.37, Calm2 x1.44, Chp1 x1.36, Atp2b1 x1.40, Atp2b2 x1.78, Slc8a1 x1.91, Camk4 x3.66, Rapgef4 x2.21, Rap1a x1.28, Map2k1 x1.44, Mapk8 x1.27, Mapk9 x2.65, Vav3 x13.5, Tiam1 x1.74, Creb3l2 x2.23).

Conclusions: Chronic GC withdrawal drives corticotroph cells into a sustained high-output state by dampening proximal receptor-proximal signaling while remodeling Ca²⁺-dependent networks to maintain increased Pomc induction and ACTH production.

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