Dual roles for Id4 in the regulation of estrogen signaling in the mammary gland and ovary

Abstract

The HLH transcriptional regulator Id4 exerts important roles in different organs, including the neural compartment, where Id4 loss usually results in early lethality. To explore the role of this basally restricted transcription factor in the mammary gland, we generated a cre-inducible mouse model. MMTV-or K14-cre-mediated deletion of Id4 led to a delay in ductal morphogenesis, consistent with previous findings using a germ-line knockout mouse model. A striking increase in the expression of ERα (Esr1), PR and FoxA1 was observed in both the basal and luminal cellular subsets of Id4-deficient mammary glands. Together with chromatin immunoprecipitation of Id4 on the Esr1 and Foxa1 promoter regions, these data imply that Id4 is a negative regulator of the ERα signaling axis. Unexpectedly, examination of the ovaries of targeted mice revealed significantly increased numbers of secondary and antral follicles, and reduced Id4 expression in the granulosa cells. Moreover, expression of the cascade of enzymes that are crucial for estrogen biosynthesis in the ovary was decreased in Id4-deficient females and uterine weights were considerably lower, indicating impaired estrogen production. Thus, compromised ovarian function and decreased circulating estrogen likely contribute to the mammary ductal defects evident in Id4-deficient mice. Collectively, these data identify Id4 as a novel regulator of estrogen signaling, where Id4 restrains ERα expression in the basal and luminal cellular compartments of the mammary gland and regulates estrogen biosynthesis in the ovary.

Inhibitor of differentiation 4 (ID4): From development to cancer

“…The cross between MMTV- Cre which directs the expression primarily to secretory epithelium of virgin and lactating mammary gland, the salivary gland, seminal vesicle, skin, erythrocytes, B cells and T cells or K-14-Cre (KRT14-Cre) with expression primarily in ectoderm and its derivatives was used to understand the role of ID4 knockout on mammary gland development and ovarian function. The mammary gland phenotype in this model was essentially similar to that of the global Id4 KO model discussed above, that is delay in ductal morphogenesis, in part due to increase in the expression of estrogen receptor-α (ERα), progesterone receptor (PR) and FOXA1 [35]. In the ovary, Id4 is expressed in the granulosa cells of secondary and antral follicles.…”

“…Recently, the entire reading frame of Id4 (exons 1 and 2) flanked by LoxP sites was created [35]. This model is a significant step forward in developing tissue specific Id4 knockouts using targeted expression of Cre recombinase.…”

“…Consequently, lack of Id4 resulted in a significant increase in the numbers of secondary and antral follicles as well as atretic (degenerating) follicles. The authors attributed the ovarian phenotype in Id4-/- mice due to decreased estrogen biosynthesis [35]. …”

“…In a ChIP study, ID4 was found to be part of the transcriptional complex that could potentially regulate ERα and Foxa1 (Table I). The lack of ID4 DNA binding domain in ID4 suggests that it most likely regulates transcription as part of a larger protein complex [35]. …”

A systems approach to renal inflammation in SLE

“…Loss of Id4 in B cells enhances cell proliferation triggered by CpG oligonucleotides and decreases sensitivity to dexamethasone-mediated apoptosis (77). ID4 regulates cell differentiation in multiple cell types and also enhances estrogen production and signaling (78); how this influences the course of LN is currently unknown. ITGAM encodes for the alpha chain of the CD11b (complement receptor 3) adhesion molecule that is expressed on myeloid cells and has both protective and pro-inflammatory functions in inflammation (79, 80).…”