tion of this pathway during cardiac organogenesis. Most aspects of cardiac development were normal, but there was a factor of
2.5 increase in heart size. The massive growth
was attributable to hyperplasia (cell number) and not hypertrophy (cell size), was evident by mid-gestation, and affected both the
left and right ventricle, compartments whose
developmental origins involve separate spatial fields, signals, and transcriptional mechanisms. Fibroblasts and smooth muscle cells in
the heart were unaffected, as were cardiac progenitor cells, and no effect on apoptosis was
seen. Ablation of Salv was inferred to affect
cardiac muscle cells but not their precursors,
and to involve cell division, not cell survival.
And conditional deletions of Mst1/2 pathway
kinases—either Mst1/2 or just Lats2 (mouse
ortholog of Wrts)—resulted in similar myocardial expansion.
Heallen et al. determined that in the
absence of Salv, numerous genes controlled
by the transcription factor β-catenin had
increased expression, reflecting increased
activity of a signaling pathway controlled
by Wnt family growth factors. Recently,
cross-talk between Mst1/2 and canonical
Wnt cascades was described in which phos-
phorylated Taz (a mouse relative of Yki) sup-
pressed canonical Wnt signals by interfer-
ing with activation of Dishevelled (Dvl1), a
component of the Wnt pathway (13). In mice
genetically engineered to have decreased
expression of both β-catenin and Salv, Heal-
len et al. observed that even partial reduc-
tion of β-catenin in cardiomyocytes rescued
muscle wall thickness, proliferation rates,
and the expression of β-catenin–dependent
genes. They also noted association between
β-catenin and nonphosphorylated Yap (which
localizes to the nucleus) in the mouse embry-
onic heart, and that the complex associates
with genes that control cell proliferation.
hold greatest importance for cardiac muscle
cell number also remain to be determined.
A further question is whether the operation of interconnected Mst1/2-Wnt pathways impinges just on cardiac muscle cell
division, or also imparts the irreversibility
of cardiac cell cycle exit. In the newborn
mouse heart, whereas regeneration remains
briefly possible, do injury signals repress
components of the proliferation-repressive
Mst1/2 pathway? Conceivably, the Mst1/2
pathway might offer therapeutic opportunities for adult cardiac myocyte renewal.
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Progranulin Resolves Inflammation
A molecule binds to a cytokine receptor and
limits the cytokine from eliciting inflammatory
responses by immune cells.
Hao Wu1 and Richard M. Siegel2
The cytokine tumor necrosis factor α (TNFα) is a major driver of rheuma- toid arthritis and related inflammatory diseases. Therapeutic agents that block
TNFα or mimic a soluble receptor for the
cytokine are effective in these diseases, but
whether other endogenous modulators of
TNFα action exist that could be targets for
therapeutic intervention is not clear. On page
478 of this issue, Tang et al. (1) show that
progranulin, a secreted molecule with some
cytokine-like properties, binds to TNF receptors and limits the action of TNFα in inflammatory arthritis.
The TNF family of cytokines in humans
comprises 19 ligands, for which there are
35 receptors. TNFα is expressed mainly by
1Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA. 2National Institute of
Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health, Bethesda, MD 20814, USA. E-mail:
endothelial and immune cells as a membrane protein that can be cleaved off the
membrane by metalloproteinases. The cytokine acts through two receptors, TNFR1 and
TNFR2. TNFR1 is broadly expressed and
promotes an inflammatory response. TNFR2
is expressed predominantly by lymphocytes
and stimulates lymphocyte activation. It also
inhibits the development and function of
“inducible” regulatory T cells (which suppress immune system activation) (2). Mouse
models of inflammatory arthritis support a
primary role for TNFR1, with some contribution by TNFR2, to the pathogenic role of
TNFα (3, 4).
Progranulin (PGRN), also known as pro-
epithelin or acrogranin, can be proteolyzed
into small homologous subunits called gran-
ulins (GRNs) or epithelins. PGRN was orig-
inally identified as an autocrine growth fac-
tor for cancer cells and fibroblasts. Muta-
tions in the human gene encoding PGRN
are associated with some cases of fronto-
temporal dementia, a neurodegenerative dis-
ease (5). Other clues suggested that PGRN
plays a role in inflammation. PGRN inhibits,
whereas GRNs stimulate, the production of
neutrophil-attracting chemokines. Cleavage
of PGRN is promoted by enzymes includ-
ing elastase, which is secreted by neutrophils.
These findings suggested a role for GRN in
amplifying acute inflammation, and PGRN
in the resolution of inflammation and wound
repair (6). Mice lacking PGRN have no overt
immunological phenotype, but PGRN-defi-
cient macrophages challenged with micro-
bial lipopolysaccharide (and other agonists
of Toll-like receptors expressed by mac-
rophages) had increased proinflammatory
cytokine production (7). But the receptors
through which PGRN mediated these anti-
inflammatory effects were unknown.