Tissue Size Regulation

A simple mechanism to sense the number N of type x cells in a tissue or organism would be to have these cells secrete a specific factor X. If each type x cell secretes X at a rate of Φ molecules per second, the average lifetime of the X molecules is T seconds, and the tissue or body volume is V, then the concentration of X will be NΦT/V. This means that there would be a roughly linear relationship between the number of type x cells and the concentration of X.

If the X factor represses proliferation of the x cells when the concentration of X is above a certain concentration, this would then regulate the number of x cells for a given total body volume. If the body volume increased or decreased, the number of x cells would change accordingly to keep the number of x cells a fixed percentage of the body volume. A key requirement of this mechanism is that the X factor is unstable. If there is a decrease (by wounding, for instance) of the number of x cells, the remaining cells will sense their absence as a decrease in X serum concentration within time T.

In the figure, a factor (red dots) secreted by the cells (yellow) binds to receptors (green). When there is the correct number of cells, a high concentration of the factor saturates the receptors, causing proliferation to stop.

One way to regulate the size of a group of cells or tissue is to have an autocrine secreted factor inhibit cell proliferation as part of a negative feedback loop. Starting in the 1930’s, a variety of experiments strongly indicated the existence of factors called chalones secreted by cells of a specific tissue that, when they reach a sufficiently high concentration in the blood, inhibit the proliferation of cells of that tissue to regulate tissue size. With the exception of myostatin, a chalone used by muscle cells, the other factors and their signal transduction pathways have eluded identification, with many purification attempts failing. We found that a Dictyostelium secreted protein we named AprA is a Dictyostelium chalone. While examining colonies of cells lacking AprA, we noticed that AprA also acts a chemorepellent. In current work, we found that a second Dictyostelium chalone is polyphosphate (~10-mer linear polymers of phosphate). We are currently using techniques such as shotgun antisense to find signal transduction components that allow cells to sense AprA and polyphosphate. Since the identity of endogenous signals that specifically regulate the size of the liver, or some other tissue, could be useful in a therapeutic setting, we hope that our work on chalones in Dictyostelium will teach us how to successfully revisit the mammalian chalone problem.

Key papers

Brock, D.A. and Gomer, R.H. (2005). A secreted factor represses cell proliferation in Dictyostelium. Development, 132, 4553-4562.

Bakthavatsalam, D., Brock, D.A., Nikravan, N.N., Houston, K.D., Hatton, R.D. and Gomer, R.H.  The secreted Dictyostelium protein CfaD is a chalone.  J. Cell Science, 121, 2473-2480 (2008).

Tang, Y. and Gomer, R.H.  A protein with similarity to PTEN regulates aggregation territory size by decreasing cAMP pulse size during Dictyostelium discoideum development.  Eukaryotic Cell, 7, 1758-1770 (2008).

Tang, Y. and Gomer, R.H.  CnrN regulates Dictyostelium group size using a counting factor-independent mechanism.  Communicative & Integrative Biology, 1, 185-187 (2008).

Choe, J. M., Bakthavatsalam, D., Phillips, J.E., and Gomer, R. H.  Dictyostelium cells bind a secreted autocrine factor that represses cell proliferation.  BMC Biochemistry, 10, 4 (2009).

Bakthavatsalam, D., Choe, J.M., Hanson, N.E. and Gomer, R.H.  A Dictyostelium chalone uses G proteins to regulate proliferation.  BMC Biology, 7, 44 (2009).

Phillips, J.E. and Gomer, R.H.  The ROCO kinase QkgA is necessary for proliferation inhibition by autocrine signals in Dictyostelium discoideum.  Eukaryotic Cell, 9, 1557-1565 (2010).

Gomer, R.H., Jang, W., and Brazill, D.  Cell density sensing and size determination.  Development, Growth & Differentiation, 53,482-494 (2011).

Phillips, J.E., Huang, E., Shaulsky, G., and Gomer, R.H.  The Putative bZIP transcription factor BzpN slows proliferation and functions in the regulation of cell density by autocrine signals in Dictyostelium. PLoS ONE, 6, e21765 (2011).

Herlihy, S.E., Tang, Y., and Gomer, R.H.  A Dictyostelium secreted factor requires a PTEN-like phosphatase to slow proliferation and induce chemorepulsion. PLoS ONE, 8, e59365 (2013).

Bakthavatsalam, D., White, M.J.V., Herlihy, S.E., Phillips, J.E., and Gomer, R.H.  A Retinoblastoma orthologue is required for the sensing of a chalone in Dictyostelium.  Eukaryotic Cell, 13, 376-382 (2014).

Phillips, J.E. and Gomer, R.H.  The p21-activated kinase (PAK) family member PakD is required for chemorepulsion and proliferation inhibition by autocrine signals in Dictyostelium discoideum.  PLoS ONE, 9, e96633 (2014).

Suess, P.M. and Gomer, R.H. Extracellular polyphosphate inhibits proliferation in an autocrine negative feedback loop in Dictyostelium discoideum.  Journal of Biological Chemistry, 291, 20260-9 (2016).

Herlihy, S.E., Tang, Y., Phillips, J.E., and Gomer, R.H.  Functional similarities between the Dictyostelium protein AprA and the human protein Dipeptidyl-Peptidase IV.  Protein Science, 26, 578-585 (2017).

Suess, P.M., Watson, J., Chen, W., and Gomer, R.H. Extracellular polyphosphate signals through Ras and Akt to prime Dictyostelium discoideum cells for development.  J. Cell Science, 130, 2394-2404 (2017).

Tang, Y., Wu, Y., Herlihy, S.E., Brito-Aleman, F.J., Ting, J.H., Janetopoulos, C., and Gomer, R.H.  An autocrine proliferation repressor regulates Dictyostelium discoideum proliferation and chemorepulsion using the G protein-coupled receptor GrlH.  mBio, 9, e02443-17 (2018).