INSIGHTS | PERSPECTIVES
sciencemag.org SCIENCEGRAPHIC: KELLIE HOLOSKI/SCIENCEmiddle ear ossicles from the jaw but main-
tain a slender bony connection to the ossified
Meckelian cartilage ( 11 , 12 ). In O. lii, the con-
nection to the ossified Meckelian cartilage is
lost and the middle ear ossicles lie separate,
likely suspended from the cranium by soft
tissue connections.
As stated by Mao et al., O. lii is evidence
for modular evolution of chewing and hear-
ing. Decoupling the two functions was cru-
cial to mammalian evolution to increase
chewing efficiency and hearing ability. De-
coupling and reducing the size of the middle
ear ossicles proved advantageous for better
sound transmission. The incorporation of
multiple delicate and mobile elements into
the middle ear cavity increased the hear-
ing sensitivity of mammals, most notably
to high-frequency sounds ( 13 ), which is con-
sidered an advantage for detecting insect
prey. High-frequency singing in insects was
already established by the mid-Jurassic, as
known from cricket fossils that show pre-
served stridulatory files with cuticular teeth
on their wings ( 14 ).
The complex process of detachment of the
middle ear ossicles happened at least three
times in the evolution of different mam-
malian lineages (Multituberculata, Mono-
tremata, and Theria) ( 15 ). In all three groups,
the middle ear ossicles became smaller and
shifted to the basicranium. Only in theri-
ans did this process enhance transverse
movement in the chewing process. Chew-
ing movements became very diverse in this
group and increased the chewing efficiency, a
phenomenon realized to an extreme in mod-
ern herbivores such as horses and camels.
In connection with the modification of the
dentition (for example, high-crowned teeth)
complex feeding adaptations were possible
within this group only by decoupling hearing
and feeding functions. j
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10.1126/science.abaCELL BIOLOGYWater loss regulates cell and
vesicle volume
Active control of vesicle water content ensures that cell size
is maintained when extracellular fluid is taken up
By Jason S. King and Elizabeth SmytheW
hen cells take up extracellular
fluid by endocytosis, they inter-
nalize a considerable proportion
of the cell volume quickly and yet
maintain their volume and ionic
composition. This is particularly
striking in the case of macropinocytosis,
which is the bulk uptake of extracellular
fluid. Through this pathway, macrophages
can be stimulated to internalize ~25% of
their cellular volume per hour into large
vacuoles known as macropinosomes. An in-
triguing question is how cells and organelles
are able to maintain their size while inter-
nalizing such large volumes. On page 301 of
this issue, Freeman et al. ( 1 ) reveal a molec-
ular mechanism underpinning homeostatic
regulation of cell size. They demonstrate
that newly formed macropinosomes rapidly
lose volume by osmosis driven by two-pore
channel (TPC)–mediated outflow of sodium
ions. This reduces hydrostatic pressure
within the macropinosome, facilitating the
extension of tubules from the macropino-
some surface and recycling of membrane
lipids and proteins back to the cell surface.
Cells need to continuously take up nu-
trients as well as signaling molecules from
their surroundings. Clathrin-dependent and
-independent endocytic pathways minimize
uptake of extracellular fluid by generating
small vesicles with a high surface area/
volume ratio, whereas macropinocytosis al-
lows cells to engulf large volumes of extra-
cellular fluid. This is especially important
in immune cells, because it enables surveil-
lance of the extracellular environment ( 2 ).
Moreover, cancer cells and many free-living
protists use this pathway to take up essen-
tial nutrients, which allows them to survive
and proliferate ( 3 , 4 ).
A universal feature of macropinosomes
is that they shrink as they mature, allowing
cells to resolve the large volumes internal-
ized. Freeman et al. show that specific loss
of sodium and chloride ions from macropi-nosomes is key for this shrinkage. They
found that this is carried out by TPCs and
is required for immune function in mice,
demonstrating its importance in vivo.
TPCs are transmembrane channels that
are specific for sodium transport and are ac-
tivated by phosphatidylinositol 3,5-bisphos-
phate [PI(3,5)P 2 ] ( 5 ), a low-abundance lipid
found on endosomes and lysosomes, the
digestive organelles of the cell. PI(3,5)P 2 is
generated by the enzyme phosphatidylinosi-Centre for Membrane Interactions and Dynamics,
Department of Biomedical Science, University of Sheffield,
Sheffield S10 2TN, UK. Email: [email protected]Recycling
to surfaceNa2+Na2+Na2+ Na2+Na2+Na2+Ion efux
drives water
lossReduced
hydrostatic
pressureShrinkage and
tubulationTPCBAR
domain
proteinsMacropinosomeMacropinocytosisExtracellular
fuidH 2 OShrinking vesicles
Macropinosome formation allows cells to take in
large volumes of extracellular fluid. To maintain cell
size, macropinosomes need to lose fluid. Two-pore
channels (TPCs) mediate efflux of sodium ions,
which drives water loss through osmosis. This allows
the recruitment of BAR domain proteins, which
facilitate the formation of narrow tubules and cell
membrane recycling.246 17 JANUARY 2020 • VOL 367 ISSUE 6475
Published by AAAS