A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression

Abstract

A dynamic and reciprocal flow of information between cells and the extracellular matrix contributes significantly to the regulation of form and function in developing systems. Signals generated by the extracellular matrix do not act in isolation. Instead, they are processed within the context of global signalling hierarchies whose constituent inputs and outputs are constantly modulated by all the factors present in the cell's surrounding microenvironment. This is particularly evident in the mammary gland, where the construction and subsequent destruction of such a hierarchy regulates changes in tissue-specific gene expression, morphogenesis and apoptosis during each developmental cycle of pregnancy, lactation and involution.

Fig. 1

A hierarchy of ECM-dependent signals regulates mammary gland development. The first tier of the hierarchy is mediated by architectural changes in cell shape that result in lactoferrin expression. The second tier of the hierarchy is mediated by laminin-specific biochemical signals that activate an ECM-responsive element (BCE-1) and induce endogenous β-casein expression. The third tier in the hierarchy is assembled during morphogenesis and serves to regulate whey acidic protein (WAP) expression and the formation of ‘alveoli’ in tissue culture models. Destruction of the hierarchy is mediated by matrix metalloproteases and results in involution. Specific signals associated with each tier of the hierarchy are outlined in Table 1. C, CCAATT/enhancer binding protein; FAK, focal adhesion kinase; MARK, mitogen-activated protein kinase; PRL, prolactin.

Fig. 2

Extracellular matrix (ECM) as an integrator of function in the mammary gland. ECM-mediated signals positively influence tissue-specific gene expression and inhibit inappropriate branching, growth, apoptosis and the development of cancer.