Metcalfe, N.B.

Monaghan, P.

Ruxton, G.D.

English

Enlighten: Publications

Nature © Macmillan Publishers Ltd 1998
8
scientific correspondence
structures, indicating that the specific inter-
action between EEA1 and PtdIns(3)P may
be vital in the control of endosome fusion.
Varsha Patki, Deirdre C. Lawe,
Silvia Corvera
Program in Molecular Medicine and
Department of Cell Biology,
University of Massachusetts Medical School,
Worcester, Massachusetts 01605, USA
e-mail: silvia.corvera@ummed.edu
Joseph V. Virbasius, Anil Chawla
Biochemistry and Molecular Biology,
University of Massachusetts Medical School,
Worcester, Massachusetts 01605, USA
1. Patki, V. et al. Proc. Natl Acad. Sci. USA 94, 7326–7330 (1997).
2. Auger, K. R. et al. Cell 57, 167–175 (1989).
3. Stenmark, H. et al. J. Biol. Chem. 271, 24048–24054 (1996).
4. Weisman, L. S. & Wickner, W. J. Biol. Chem. 267, 618–623
(1992).
5. Piper, R. C., Cooper, A. A, Yang, H. & Stevens, T. H. J. Cell. Biol.
131, 603–617 (1995).
6. Komada, M., Masaki, R., Yamamoto, A. & Kitamura, N. J. Biol.
Chem. 272, 20538–20544 (1997).
7. Zheng, Y. et al. J. Biol. Chem. 271, 33169–33172 (1996).
8. Schu, P. V. et al. Science 260, 88–91 (1993).
9. Vanhaesebroeck, B. et al. Trends Biochem. Sci. 22, 267–272
(1997).
10.Klarlund, J. K. et al. Science 275, 1927–1930 (1997).
11.Gaullier, J.-M.et al. Nature 394, 432–433 (1998).
135 amino acids of EEA1 bound increas-
ingly to liposomes containing increasing
amounts of PtdIns(3)P (Fig. 1a). Chelation
of zinc inhibited binding, indicating that
the interaction between the fusion protein
and PtdIns(3)P was through a RING zinc-
finger domain present in this carboxy-
terminal region (Fig. 1b). We saw no specific
binding to liposomes containing other
polyphosphoinositides (Fig. 1b).
A fusion protein containing GST and the
pleckstrin-homology domain of GRP-1,
which binds phosphatidylinositol-3,4,5-
trisphosophate with high affinity (Kd*1
mM) (ref. 10), bound to liposomes contain-
ing phosphatidylinositol-3,4,5-trisphos-
phate, but not to liposomes containing
PtdIns(3)P (Fig. 1b). Thus, the binding of
the EEA1 RING finger to PtdIns(3)P is spe-
cific and of high affinity. Furthermore, the
homologous domain in Hrs has been report-
ed11 to bind specifically to PtdIns(3)P. Thus
this ‘FYVE’ domain seems to constitute a
conserved binding motif for PtdIns(3)P.
A chimaera containing green fluores-
cence protein (GFP) at the carboxy termi-
nus of EEA1 (EEA1–GFP) bound to
liposomes containing PtdIns(3)P, but, in
contrast to wild-type EEA1, this chimaera
also bound to liposomes composed of
phosphatidylserine or phosphatidylserine
and phosphatidylinositol (Fig. 1c).
When transfected into Cos-1 cells,
EEA1–GFP caused the formation of lagoon-
like structures (Fig. 2), which contained
transferrin internalized from outside the
cells (not shown), indicating that the struc-
tures may represent fused endosomes.
Overexpression of wild-type EEA1 (Fig. 2,
top), or of another EEA1 chimaera contain-
ing nine amino acids of the haemaglutinnin
protein of influenza virus, did not produce
this phenotype. Thus, the loss in binding
specificity caused by GFP correlates with
the formation of abnormal endosomal
Figure 2 EAA1—GFP prevents the correct for-
mation of early endosomes. Cos-1 cells
(control is shown at top left) were transfect-
ed with wild-type EEA1 (top right), EEA1—GFP
(middle panels) or EEA1—haemagglutinin
(bottom panels). Cells were stained with
anti-EEA1 antiserum (top panels) or with
anti-haemagglutinin antiserum (bottom 
panels). EEA1—GFP intrinsic fluorescence
was visualized in unstained cells (middle
panels). Examples of cells expressing rela-
tively low (left panels) or high (right panels)
levels of each construct are shown.
education. But we believe that the evidence
presented by Pantev et al. is equally consis-
tent with other interpretations.
Pantev et al. based their report on sug-
gested correlations between the age at
which musicians first began to play an
instrument and the strength of cortical 
activation in response to piano tones when
tested as adults. But the evidence for such
correlations in their data is weak.
They present three correlations (for
musicians with absolute pitch or with rela-
tive pitch, and for both groups combined).
The (marginally significant) probability lev-
els quoted are for one-tailed tests, used
because ‘negative correlations were predict-
ed’. But it is possible that the cortical
response to sensory experience might ini-
tially increase with age in young children,
and so a positive correlation would be pre-
dicted. As both negative and positive corre-
lations are possible, two-tailed tests should
have been used in this case. Two-tailed tests
show none of the reported correlations to
be statistically significant at the traditional
5% level, and the confidence intervals for
the correlation coefficients all include zero.
Even if more extensive experiments were
to find a significant correlation, correlation
does not indicate causation. The main con-
tributors to the trends (if they exist) shown
in Pantev et al.’s Fig. 2 are the musicians
who began learning their instrument by 3–5
years of age. Musical tuition in such very
young children is almost certainly associated
with a high degree of parental musical skill
or interest. At least two other explanations
for the correlation would therefore be possi-
ble. First, perhaps only children with a par-
ticular type of cortical response to musical
sounds are capable of learning an instrument
from a very early age. Such a cortical
response may have an inherited component.
Second, it is possible that children brought
up in musical families hear more music at a
very young age, inducing more cortical reor-
ganization. Neither explanation requires the
children to have practised an instrument.
Pantev et al.’s comment that there was a
“dependence of auditory [cortical]… repre-
sentations on practice beginning before the
age of about 10 years” ignores genotypic
and environmental influences. It will be
possible to establish the true nature of any
relationship only by controlling for these
effects. In the meantime, given our current
state of knowledge, those wanting musical
children might be well advised to examine
carefully the musical abilities and compact-
disc collections of potential mates, rather
than investing in expensive music lessons
for reluctant three-year-olds.
Pat Monaghan, Neil B. Metcalfe,
Graeme D. Ruxton
Institute of Biomedical and Life Sciences,
Graham Kerr Building, Glasgow University,
Glasgow G12 8QQ, UK
Pantev et al. (Nature 392, 811–814; 1998)
suggest that the degree of cortical reorgani-
zation and enhancement of the cortical
response to musical notes depends on the
age at which musicians first begin learning to
play an instrument. Specifically, the younger
the subjects were when they started to play,
the larger was their cortical reorganization in
recognition of piano tones. In addition to its
biological interest, such a finding, if true,
would have great implications for musical
Does practice shape 
thebrain?
434 NATURE | VOL 394 | 30 JULY 1998


Does practice shape the brain?

Pat Monaghan

Neil B. Metcalfe

Graeme D. Ruxton

Crossref

Enlighten

Nature © Macmillan Publishers Ltd 19988scientific correspondencestructures, indicating that the specific inter-action between EEA1 and PtdIns(3)P maybe vital in the control of endosome fusion.Varsha Patki, Deirdre C. Lawe,Silvia CorveraProgram in Molecular Medicine andDepartment of Cell Biology,University of Massachusetts Medical School,Worcester, Massachusetts 01605, USAe-mail: silvia.corvera@ummed.eduJoseph V. Virbasius, Anil ChawlaBiochemistry and Molecular Biology,University of Massachusetts Medical School,Worcester, Massachusetts 01605, USA1. Patki, V. et al. Proc. Natl Acad. Sci. USA 94, 7326–7330 (1997).2. Auger, K. R. et al. Cell 57, 167–175 (1989).3. Stenmark, H. et al. J. Biol. Chem. 271, 24048–24054 (1996).4. Weisman, L. S. & Wickner, W. J. Biol. Chem. 267, 618–623(1992).5. Piper, R. C., Cooper, A. A, Yang, H. & Stevens, T. H. J. Cell. Biol.131, 603–617 (1995).6. Komada, M., Masaki, R., Yamamoto, A. & Kitamura, N. J. Biol.Chem. 272, 20538–20544 (1997).7. Zheng, Y. et al. J. Biol. Chem. 271, 33169–33172 (1996).8. Schu, P. V. et al. Science 260, 88–91 (1993).9. Vanhaesebroeck, B. et al. Trends Biochem. Sci. 22, 267–272(1997).10.Klarlund, J. K. et al. Science 275, 1927–1930 (1997).11.Gaullier, J.-M.et al. Nature 394, 432–433 (1998).135 amino acids of EEA1 bound increas-ingly to liposomes containing increasingamounts of PtdIns(3)P (Fig. 1a). Chelationof zinc inhibited binding, indicating thatthe interaction between the fusion proteinand PtdIns(3)P was through a RING zinc-finger domain present in this carboxy-terminal region (Fig. 1b). We saw no specificbinding to liposomes containing otherpolyphosphoinositides (Fig. 1b).A fusion protein containing GST and thepleckstrin-homology domain of GRP-1,which binds phosphatidylinositol-3,4,5-trisphosophate with high affinity (Kd*1mM) (ref. 10), bound to liposomes contain-ing phosphatidylinositol-3,4,5-trisphos-phate, but not to liposomes containingPtdIns(3)P (Fig. 1b). Thus, the binding ofthe EEA1 RING finger to PtdIns(3)P is spe-cific and of high affinity. Furthermore, thehomologous domain in Hrs has been report-ed11 to bind specifically to PtdIns(3)P. Thusthis ‘FYVE’ domain seems to constitute aconserved binding motif for PtdIns(3)P.A chimaera containing green fluores-cence protein (GFP) at the carboxy termi-nus of EEA1 (EEA1–GFP) bound toliposomes containing PtdIns(3)P, but, incontrast to wild-type EEA1, this chimaeraalso bound to liposomes composed ofphosphatidylserine or phosphatidylserineand phosphatidylinositol (Fig. 1c).When transfected into Cos-1 cells,EEA1–GFP caused the formation of lagoon-like structures (Fig. 2), which containedtransferrin internalized from outside thecells (not shown), indicating that the struc-tures may represent fused endosomes.Overexpression of wild-type EEA1 (Fig. 2,top), or of another EEA1 chimaera contain-ing nine amino acids of the haemaglutinninprotein of influenza virus, did not producethis phenotype. Thus, the loss in bindingspecificity caused by GFP correlates withthe formation of abnormal endosomalFigure 2 EAA1—GFP prevents the correct for-mation of early endosomes. Cos-1 cells(control is shown at top left) were transfect-ed with wild-type EEA1 (top right), EEA1—GFP(middle panels) or EEA1—haemagglutinin(bottom panels). Cells were stained withanti-EEA1 antiserum (top panels) or withanti-haemagglutinin antiserum (bottom panels). EEA1—GFP intrinsic fluorescencewas visualized in unstained cells (middlepanels). Examples of cells expressing rela-tively low (left panels) or high (right panels)levels of each construct are shown.education. But we believe that the evidencepresented by Pantev et al. is equally consis-tent with other interpretations.Pantev et al. based their report on sug-gested correlations between the age atwhich musicians first began to play aninstrument and the strength of cortical activation in response to piano tones whentested as adults. But the evidence for suchcorrelations in their data is weak.They present three correlations (formusicians with absolute pitch or with rela-tive pitch, and for both groups combined).The (marginally significant) probability lev-els quoted are for one-tailed tests, usedbecause ‘negative correlations were predict-ed’. But it is possible that the corticalresponse to sensory experience might ini-tially increase with age in young children,and so a positive correlation would be pre-dicted. As both negative and positive corre-lations are possible, two-tailed tests shouldhave been used in this case. Two-tailed testsshow none of the reported correlations tobe statistically significant at the traditional5% level, and the confidence intervals forthe correlation coefficients all include zero.Even if more extensive experiments wereto find a significant correlation, correlationdoes not indicate causation. The main con-tributors to the trends (if they exist) shownin Pantev et al.’s Fig. 2 are the musicianswho began learning their instrument by 3–5years of age. Musical tuition in such veryyoung children is almost certainly associatedwith a high degree of parental musical skillor interest. At least two other explanationsfor the correlation would therefore be possi-ble. First, perhaps only children with a par-ticular type of cortical response to musicalsounds are capable of learning an instrumentfrom a very early age. Such a corticalresponse may have an inherited component.Second, it is possible that children broughtup in musical families hear more music at avery young age, inducing more cortical reor-ganization. Neither explanation requires thechildren to have practised an instrument.Pantev et al.’s comment that there was a“dependence of auditory [cortical]… repre-sentations on practice beginning before theage of about 10 years” ignores genotypicand environmental influences. It will bepossible to establish the true nature of anyrelationship only by controlling for theseeffects. In the meantime, given our currentstate of knowledge, those wanting musicalchildren might be well advised to examinecarefully the musical abilities and compact-disc collections of potential mates, ratherthan investing in expensive music lessonsfor reluctant three-year-olds.Pat Monaghan, Neil B. Metcalfe,Graeme D. RuxtonInstitute of Biomedical and Life Sciences,Graham Kerr Building, Glasgow University,Glasgow G12 8QQ, UKPantev et al. (Nature 392, 811–814; 1998)suggest that the degree of cortical reorgani-zation and enhancement of the corticalresponse to musical notes depends on theage at which musicians first begin learning toplay an instrument. Specifically, the youngerthe subjects were when they started to play,the larger was their cortical reorganization inrecognition of piano tones. In addition to itsbiological interest, such a finding, if true,would have great implications for musicalDoes practice shape thebrain?434 NATURE | VOL 394 | 30 JULY 1998

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Does practice shape the brain?

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