Physiology Adult Organ Growth

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Two articles this week look at the mechanisms by which organs in the adult can grow in response to loss or increased demand. Otu et al. performed microarray expression profiling to compare the transcription patterns associated with partial hepatectomy and embryonic liver development in mice. The transcriptional profiles of regenerating liver and developing liver were very different based on principal component analysis, a computational method that simplifies multivariate data. Most of the genes that were common to both conditions and that exhibited increased expression were classified as involved in cell proliferation. Developing liver profiles showed increased expression of genes involved in chromatin remodeling, which tapered off as the embryos matured. The transcription factors regulated in each condition were also predominantly different. Otu et al.’s results suggest that liver regeneration does not involve recapitulation of pathways involved in liver biogenesis during development.

In the pancreas, increased cell mass also occurs in adults in response to increased metabolic demand, and defects in this process are noted in type 2 diabetes. Analysis of the genetic basis of maturity-onset diabetes of the young (MODY) revealed multiple transcription factors as contributing to this form of type 2 diabetes. Gupta et al. explored the transcriptional profile regulated by one of these MODY-causing genes, the gene encoding the orphan nuclear receptor hepatocyte nuclear factor-4 (HNF-4), by performing microarray analysis of pancreatic islets from wild-type mice or mice deficient for HNF-4. Although the cell mass in the 4-month-old HNF-4-deficient mice was unchanged, transcriptional profiling suggested that HNF-4 was implicated in cell proliferation. To determine whether HNF-4 was involved in cell expansion in response to demand, the authors monitored cell mass in mice in response to pregnancy, which is a natural process that increases metabolic demand and stimulates cell expansion. cell mass and pancreatic insulin content were reduced in the HNF-4-mutant pregnant mice compared with that in wild-type mice, and the pancreatic islets showed decreased cell division based on BrdU labeling. Both virgin and pregnant mice deficient in HNF-4 exhibited impaired glucose tolerance, with the pregnant mice showing a more severe impact. One of the genes exhibiting decreased expression in the HNF-4-mutant mice encoded ST5, which is similar to guanine nucleotide exchange factors (GEFs). Chromatin immunoprecipitation experiments along with reporter gene expression confirmed that ST5 is regulated by HNF-4. Knockdown of ST5 with RNAi decreased basal and epidermal growth factor (EGF)-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the cell line MIN6. In islets from the HNF-4-mutant mice, GTP-bound Ras was decreased and phosphorylation of ERK in both the basal and EGF-stimulated conditions was also decreased. ERK activation was also impaired in the pregnant HNF-4 mice. Thus, HNF-4 appears to be important for stimulating cell mass in the adult in response to increased metabolic demand, and this may be mediated through the stimulation of the expression of the gene encoding the Ras GEF ST5.

H. H. Otu, K. Naxerova, K. Ho, H. Can, N. Nesbitt, T. A. Libermann, S. J. Karp, Restoration of liver mass after injury requires proliferative not embryonic transcriptional patterns. J. Biol. Chem. 282, 11197-11204 (2007). [Abstract] [Full Text]

R. K. Gupta, N. Gao, R. K. Gorski, P. White, O. T. Hardy, K. Rafiq, J. E. Brestelli, G. Chen, C. J. Stoeckert Jr., K. H. Kaestner, Expansion of adult -cell mass in response to increased metabolic demand is dependent on HNF-4. Genes Dev. 21, 756-769 (2007). [Abstract] [Full Text]