Bmp7 regulates branching morphogenesis of the lacrimal gland by promoting mesenchymal proliferation and condensation

Abstract

The lacrimal gland provides an excellent model with which to study the epithelial-mesenchymal interactions that are crucial to the process of branching morphogenesis. In the current study, we show that bone morphogenetic protein 7 (Bmp7) is expressed with a complex pattern in the developing gland and has an important role in regulating branching. In loss-of-function analyses, we find that Bmp7-null mice have distinctive reductions in lacrimal gland branch number, and that inhibition of Bmp activity in gland explant cultures has a very similar consequence. Consistent with this,exposure of whole-gland explants to recombinant Bmp7 results in increased branch number. In determining which cells of the gland respond directly to Bmp7, we have tested isolated mesenchyme and epithelium. We find that, as expected, Bmp4 can suppress bud extension in isolated epithelium stimulated by Fgf10, but interestingly, Bmp7 has no discernible effect. Bmp7 does, however,stimulate a distinct response in mesenchymal cells. This manifests as a promotion of cell division and formation of aggregates, and upregulation of cadherin adhesion molecules, the junctional protein connexin 43 and ofα-smooth muscle actin. These data suggest that in this branching system,mesenchyme is the primary target of Bmp7 and that formation of mesenchymal condensations characteristic of signaling centers may be enhanced by Bmp7. Based on the activity of Bmp7 in promoting branching, we also propose a model suggesting that a discrete region of Bmp7-expressing head mesenchyme may be crucial in determining the location of the exorbital lobe of the gland.

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

“…All primary microarray data are accessible at www.ncbi.nlm.nih.gov/geo (GSE7382). We selected BMP7 for further study because BMP7 mediates epithelial-mesenchymal signaling (Dean et al, 2004), and epithelial cell apoptosis and proliferation in several different organ systems (Luo et al, 1995;Monroe et al, 2000). Consistent with these observations, we found that BMP7 can decrease proliferation and increase apoptosis of normal and cancerous mammary epithelial cells (Supplementary Figure S8).…”

“…Finally, it is likely that LMO4 effects are context-dependent; LMO4-mediated signaling to stroma and/or other neighboring cells may be important for the pro-proliferative and pro-tumorigenic effects of LMO4 upregulation in vivo. In this regard, the identification of BMP7 as a target gene of LMO4 is relevant because BMP7 has striking effects on stromal cells (Dean et al, 2004), and it is known that growth signaling from stromal fibroblasts during mammary gland development is regulated by TGFb ligands (Cheng et al, 2005). Like LMO4, BMP7 is highly expressed in the ductular end buds of the developing mammary gland (Sum et al, 2005a, b), the site of active proliferation and stromal invasion of the mammary epithelium.…”

Organogenesis of the juxta‐oral organ in mice

“…In the heterozygous and homozygous strains of this mutant line, lacZ is expressed in various epithelial and mesenchymal tissues. Expression is detected, in the craniofacial area, such as in the retinal pigmented epithelium, ocular surface ectoderm and orbital mesenchymal tissue (Godin et al 1998), skin (except keratinized layer) and oral epithelium, epithelia of parotid duct and gland (our observation), submandibular gland epithelium (Jaskoll et al 2002), and mesenchyme of lacrimal gland (Dean et al 2004). Homozygotes of this mutant have several abnormal phenotypes, such as in the eyes and kidneys, and will die at birth.…”

“…During our study on lacrimal gland (Dean et al 2004) using this allele, we found that lacZ is expressed in the epithelial parenchyma of the JOO as well as in salivary glands. We considered, therefore, that the organ can be visualized easily by whole-mount β -gal staining.…”

Neural crest derivatives in ocular and periocular structures

“…Surprisingly, this mutation also results in the loss of eyelid along with conspicuous corneal defects (Lan et al, 2004). Besides, using transgenic aproach, Dean and coworkers have recently shown that the morphogen Bmp7 is highly expressed in eyelid mesenchyme (Dean et al, 2004). As evoked before, given the involvement of Tgfβ family members and their respective antagonists in specifying the anterior eye segment, it is tempting to hypothesize that Bmp7 could partly determine the fate of neural crest cells and/or regulate their myogenic potential at this level.…”