Small Animals, Small Cells: Miniature mice reveal connection between cell size and longevity pathways (Insulin-related signaling; Body size)
Authors: Beckman Mary 
Published: August 2003

Bigger might be better for roller coasters but perhaps not for living things: Within a species, petite individuals tend to live longer. No one knows why they do, but many scientists have assumed that wee creatures have fewer cells than their larger relatives--and therefore their cells don't have as many opportunities to turn cancerous, for example. New work suggests that littler animals have tinier, not fewer, cells. The findings also show that a biochemical pathway that determines cell size taps into a life-span-influencing hormonal system, raising the eyebrows of longevity researchers.

Toy poodles run longevity rings around Great Danes; small horses, rats, and mice also endure (see
Warner Perspective
). Long-lived mutant mice are about a third smaller than their normal counterparts (see
Ames Dwarf
,
Laron
,
Little
,
and
Snell Dwarf
mice). Mutations in those mice (see
Prop1
,
GHR
,
Ghrhr
, and
Pit1
) hamper hormones--insulin and insulin-like-growth factor-1 (IGF-1)--that regulate metabolism and promote growth. The animals' daintiness might result from those disruptions. However, the relation between IGF-1 signaling, animal size, and long life remains puzzling.

A serendipitous discovery in another field might provide clues. To understand the role of a protein called RhoGAP during embryonic development, Sordella and colleagues created mice without the molecule, which operates in a biochemical pathway known to shape cells. Newborn mice lacking RhoGAP were 30% smaller than their normal littermates, sported proportionally shrunken organs, and died immediately after birth. By sending cells from normal-sized and miniature organs through a cell-sorting machine, the researchers found that the mutant mice harbored a full complement of cells but that each cell was more compact than normal. RhoGAP thwarts a protein called Rho, which prods genes required for neuronal growth in an embryo, among other activities. To test whether RhoGAP controls size through Rho, the team cultured cells from the mutant mouse and added a chemical that shuts Rho off. Treated cells assumed a normal volume, indicating that the opposing forces of RhoGAP and Rho together govern cell size.
Further experiments link the Rho pathway and the hormonal pathway that is crippled in dwarf mice. The mutant animals resembled mice lacking a protein called CREB, which the IGF-1 pathway activates. So the researchers investigated whether a dearth of RhoGAP crippled CREB. In cells without RhoGAP, IGF-1 could not activate CREB. Taken together, these results reveal a new connection between Rho, IGF-1, and cell size.
The Rho pathway's link to IGF-1 intrigues researchers who study life-span. Because mice without RhoGap die young, they won't be useful in aging studies, says Steven Austad, a comparative biologist at the University of Idaho in Moscow, but the result challenges the assumption that dwarf mice have fewer cells than normal. Regardless of whether future work links hyperactive Rho to the small stature of long-lived animals, says biogerontologist Richard Miller of the University of Michigan, Ann Arbor, understanding how body size is regulated might help tease apart the relation of IGF-1, longevity, and body mass. Scientists hope such revelations will explain why small creatures are big on survival.
--Mary Beckman

R. Sordella, M. Classon, K.-Q. Hu, S. F. Matheson, M. R. Brouns, B. Fine, L. Zhang, H. Takami, Y. Yamada, J. Settleman, Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.
Dev. Cell
,
2
, 553-565 (2002).
[Abstract]
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