Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Li, Jiarong; Sun, Huayan; Feltri, M. Laura; Mercurio, Arthur M.

doi:10.1016/j.ydbio.2015.09.015

Cited by 13 publications

(9 citation statements)

References 26 publications

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“…No integrin-related gene was significantly altered by adjusted p-value, but Itga3, Itgb4, and Itgb7 were significantly altered by p-value. Analysis of their expression levels by qRT-PCR at puberty in mammary glands from WT and Adamts18 −/− mice showed Itga3 and Itgb4, two integrins previously implicated in mammary stem cell function 47,48 and part of laminin 5 receptors, to be significantly down modulated in the mutants (Fig. 7d).…”

Section: Resultsmentioning

confidence: 91%

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

et al. 2020

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Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membranespecific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation.

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Section: Resultsmentioning

confidence: 91%

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

et al. 2020

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“…The mechanisms of milk secretion are multifaceted and complex. Over the past few decades, studies with ruminants have focused on histological analysis and the study of hormone levels to evaluate the physiological function of lactation, but more rarely has the process been studied at the molecular level (Binder et al, ; Giraddi et al, ; Li, Sun, Feltri, & Mercurio, ). This study attempted to determine the function and mechanism of miR‐135b in prolactin (PRL) pushing lactation in goat mammary epithelial tissue.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of prolactin inhibition of miR‐135b via methylation in goat mammary epithelial cells

Chen¹,

Luo²,

Zhang³

et al. 2017

Journal Cellular Physiology

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Prolactin is an important endocrine activator of lactogenesis. This study investigated the function and mechanism of miR-135b in the enhancement of lactation by prolactin in goat mammary epithelial tissue. We utilized S-Poly (T) sequencing to evaluate changes in gene regulation in the goat mammary gland after incubation with 2.5 μg/ml prolactin and 2.5 μg/ml IGF-1 by examining highly expressed miRNAs during early lactation and late-lactation. The results illustrated that miR-135b is highly expressed in the goat mammary gland during early lactation and late-lactation, and also after treatment with 2.5 μg/ml prolactin and 2.5 μg/ml IGF-1. We used Q-RT PCR, Western Blot, immunofluorescence, and luciferase reporter assay analysis, and found that PRL was significantly down-regulated in response to the expression of miR-135b in a manner that was functionally related to TAG synthesis via the large tumor suppressor 2 gene (Lats2), an important regulator of adipocyte proliferation via Hippo Signaling. Furthermore, using bisulfite-sequencing PCR (BSP), Q-PCR, and Western Blot we discovered an increase in expression of DNMT I (DNA methyl transferase I) in goat mammary epithelial cells with the 2.5 μg/ml PRL incubation, which led to DNA methylation of the CpG island upstream of miR-135b and inhibited the transcription and expression of miR-135b. K E Y W O R D Sfat metabolism, LATS2, methylation, miR-135b | INTRODUCTIONMilk provides optimal nutrition for growth and development of humans. Compared with cow milk, goat milk (the milk of Capra hircus) has a higher level of unsaturated fatty acids, total fat, calcium, vitamins, carbohydrates, and proteins (Han et al., 2004;Hinrichs, 2004;Luna, Bach, Juarez, & de la Fuente, 2008;Qu, Chen, Fan, Sun, & Zeng, 2016).Prolactin (PRL) plays a key role in the process of lactation and is secreted by the hypothalamus. PRL is an important hormone for the initiation of lactation in ruminants, can stimulate mammary epithelial cell metabolism, and stimulate milk protein synthesis (Inaba et al., 2016). In non-ruminants, PRL promotes mammary development during early pregnancy by stimulation of the ovaries to produce estrogen and progesterone (Campo Verde Arbocco et al., 2016).During pregnancy, PRL concentrations in plasma are significantly elevated and it can promote the secretion of IGF 1 and enhance the activity of the PKB/AKt (protein kinase) pathway (Roman, Seres, Herichova, Zeman, & Jurcovicova, 2003; Milewicz et al., 2011;Xiong et al., 2016). In addition, PRL-PRLR complexes (PRL combined with PRLR) can enter cells and elicit physiological effects through the JAK/ STAT and PKB/AKt pathway (Akers, 2006). Numerous studies have revealed that PRL plays an indispensable role in the process of lactation. However, how PRL works at the molecular level and the related molecular mechanism remain a "black box" that requires careful research (Akers, 2006;Erb et al., 1976;Hart, Bines, Morant, & Ridley, 1978;Kazmer & Oyler, 1991 Wang et al., 2014). MiRNA regulation is precise and its expression has stri...

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“…The only other branching organ where integrin α6β4 was shown to be important is the mammary gland. Deleting β4 resulted in small glands that had increased apoptosis in the surrounding mesenchyme due to decreased PTHrP expression and signaling[35], however these results contrast with another study where mammary glands were shown to develop normally in integrin α6-null mice[36]. Similar to our results, deleting the β4 integrin subunit in Schwann cells in peripheral nerves resulted in abnormal myelin folding and slower nerve recovery after injury because integrin α6β4 is required to anchor Schwann cells to the basal lamina[37, 38].…”

Section: Discussionmentioning

confidence: 99%

Integrin alpha6 maintains the structural integrity of the kidney collecting system

Viquez

Yazlovitskaya

et al. 2017

Matrix Biology

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Laminins are a major constituent of the basement membranes of the kidney collecting system. Integrins, transmembrane receptors formed by non-covalently bound α and β subunits, serve as laminin receptors, but their role in development and homeostasis of the kidney collecting system are poorly defined. Integrin α3β1, one of the major laminin receptors, plays a minor role in kidney collecting system development, while the role of α6 containing integrins (α6β1 and α6β4), the other major laminin receptors, is unknown. Patients with mutations in α6 containing integrins not only develop epidermolysis bullosa, but also have abnormalities in the kidney collecting system. In this study, we show that selectively deleting the α6 or β4 integrin subunits at the initiation of ureteric bud development in mice does not affect morphogenesis. However, the collecting system becomes dilated and dysmorphic as the mice age. The collecting system in both null genotypes were also highly susceptible to unilateral ureteric obstruction injury with evidence of excessive tubule dilatation and epithelial cell apoptosis. Mechanistically, integrin α6-null collecting duct cells are unable to withstand high mechanical force when adhered to laminin. Thus, we conclude that α6 integrins are important for maintaining the integrity of the kidney collecting system by enhancing tight adhesion of the epithelial cells to the basement membrane. These data give a mechanistic explanation for the association between kidney collecting system abnormalities in patients and epidermolysis bullosa.

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Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Cited by 13 publications

References 26 publications

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

Mechanism of prolactin inhibition of miR‐135b via methylation in goat mammary epithelial cells

Integrin alpha6 maintains the structural integrity of the kidney collecting system

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