Sequential signals choreograph embryonic tubule formation

A new research study demonstrates that a single chemical growth factor orchestrates a complex developmental process by sequentially activating distinct subsets of molecular signals. The research, published in the July issue of Developmental Cell, provides new insight into the carefully controlled architectural changes that underlie organ development.

During development, chemical signals such as hepatocyte growth factor (HGF) cause individual cells to migrate to different locations, increase in number and differentiate into mature cells during tubule formation in the kidney, liver and breast. All of these cellular changes must be carefully coordinated over space and time. Dr. Keith E. Mostov from the Department of Anatomy at the University of California, San Francisco, and colleagues investigated the HGF-stimulated molecular mechanisms that are required for coordination of these cellular behaviors. The researchers used Madin-Darby canine kidney (MDCK) cells grown in collagen gels and stimulated with HGF. This experimental protocol results in the formation of branching tubules that resemble the development of tubules in many organs in vivo and allows for examination of molecular events that occur during tubulogenesis. "We found that downstream targets of HGF coordinately regulate successive stages of tubule development," says Dr. Mostov. "Activation of extracellular-regulated kinase (ERK) is necessary and sufficient for the initial stage when the cells migrate but ERK is not required later on when the cells differentiate. Conversely, matrix metalloproteases (MMPs) are required for the differentiation stage but not the initial migration phase."

The researchers conclude that HGF directs the complex process of tubule development by dividing it into two distinct phases that are controlled by different molecular signals provided by ERK and MMPs. According to Dr. Mostov, "Proper timing and sequence of cellular events is crucial for successful morphogenesis of multicellular structures. Our results demonstrate how HGF can induce distinct regulatory subprograms that act at different times and effect different morphological outcomes." The authors point out that other research has implicated ERK and MMP as playing a key role in the generation of other organs and suggest that is possible that growth factor induced ERK and MMP subprograms could underlie tubule development in other systems.

Lucy Erin O'Brien, Kitty Tang, Ellen S. Kats, Amy Schutz-Geschwender, Joshua H. Lipschutz, and Keith E. Mostov: "ERK and MMPs Sequentially Regulate Distinct Stages of Epithelial Tubule Development"

Publishing in Developmental Cell, Volume 7, Number 1, July 2004, pages 21-32.

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