Expansion and reduction of maternal β-cells during pregnancy and postpartum is a physiologic example of rapid and dynamic changes in β-cell mass occurring outside of organism development (Baeyens et al., 2016; Rieck et al., 2010; Ruiz-Otero et al., 2024). Thus, elucidation of molecular mediators governing these processes has the potential to yield new insights into how the amount of functional β-cell mass is controlled. Furthermore, as deficiency of functional β-cells is a key component of diabetes pathogenesis, mechanisms regulating functional β-cell mass has therapeutic potential to impact disease management (Aguayo-Mazzucato et al., 2018; Bakhti et al., 2022; Kerper et al., 2022).

Regulators of gestational β-cell mass expansion have been identified in rodent models, including through transcriptomic studies (Chung et al., 2023; Kim et al., 2010; Layden et al., 2010; Pepin et al., 2019; Rieck et al., 2009). However, very few studies have examined how β-cell mass is restored to levels comparable to pre-pregnancy following parturition, also known as postpartum “regression” of β-cell mass (Demirci et al., 2012; Scaglia et al., 1995; Takahashi et al., 2020). The cellular mechanism of regression remains controversial and has been reported to occur via reduction in β-cell size, increased β-cell apoptosis, and macrophage phagocytosis of β-cells (Scaglia et al., 1995; Takahashi et al., 2020; Endo et al., 2023). Lactogen signaling, which activates PRLR, is most widely known for regulating milk production in the mammary glands but is also a critical regulator of gestational β-cell adaptations, including expanded β-cell mass and insulin secretion needed to maintain gestational glucose homeostasis (Kim et al., 2010; Banerjee et al., 2016; Huang et al., 2009; Nteeba et al., 2019). Recent studies have revealed that lactogen-signaling, via downstream serotonin production also regulates β-cells in the postpartum and lactating periods (Takahashi et al., 2020; Moon et al., 2020). However, a comprehensive examination of signals and mechanisms contributing to postpartum regression has not been performed.

To address this question, we recently used single-cell RNA sequencing to identify transcriptional changes within maternal islets in mice from non-pregnant, pregnant and postpartum states (Chung et al., 2023). We found that multiple immediate early genes were induced in β-cells during late pregnancy and early postpartum, including c-Jun.

c-Jun is a transcription factor that is a member of the AP-1 transcription family with established roles in regulating proliferation, apoptosis, and survival in multiple cell types and contexts (Li et al., 2024; Shaulian et al., 2001). However, only a handful of studies have examined c-Jun or AP-1 function in β-cell lines or murine islets, and none have examined c-Jun or other AP-1 components in pregnancy or postpartum adaptations. For example, studies of INS-1 and MIN6 cells stimulated with glucose and cAMP found induction of IEGs including c-Fos, c-Jun, JunB and nur-77 (aka Nr4a1) by glucose and GLP-1 cotreatment, and validated direct regulation of only a single downstream target gene, Srxn1 by c-Fos (Glauser et al., 2007; Susini et al., 1998).

Here we examine c-Jun regulation in gestational and postpartum islets, and how it regulates islet responses to pro-apoptotic stress, and find that c-Jun, downstream of PRLR and MAPK signaling directly regulates survival from a pro-apoptotic stressor in murine and human islets. c-Jun pro-survival effects are contributed to by induction of pro-survival genes Birc5 and Bcl2l1.