core and the elastic response of the surrounding
Out-of-plane grain rotation and surface tilting
are expected to influence technically important
properties of NC metal films and wires that are
size-dependent and sensitive to GB structure
(2, 3). For example, the resistivity of Cu wires
increases precipitously with decreasing the diameter because of increased contributions from
interfacial scattering and surface roughness as
the grain size falls below the mean free path
(~40 nm in Cu) (2, 14). This work suggests that
grain rotation and tilting can be modulated by
engineering SF energy through GB doping and/or
controlling the film-substrate interaction so as
to provide a potential means to manipulate the
properties of NC metals.
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J.J.B. acknowledges the Science Foundation Ireland (SFI)–funded
Principal Investigator Award (grant 12/IA/1482); this work
emanated from research supported in part by a research grant
from SFI under grant SFI/12/RC/2278. D.J.S. acknowledges
support of the National Science Foundation Division of Materials
Research through award 1507013. A.P.S. is grateful to the
Department of Physics at Imperial College London for the provision
of laboratory facilities. All data are reported in the main paper
and supplementary materials.
Figs. S1 and S2
20 April 2017; accepted 21 June 2017
Control of species-dependent
underlying manual dexterity
Zirong Gu,1 John Kalamboglas,2,3 Shin Yoshioka,1 Wenqi Han,4 Zhuo Li,4,5
Yuka Imamura Kawasawa,4,6 Sirisha Pochareddy,4 Zhen Li,4 Fuchen Liu,4 Xuming Xu,4
Sagara Wijeratne,7 Masaki Ueno,1,8 Emily Blatz,1 Joseph Salomone,1
Atsushi Kumanogoh,9 Mladen-Roko Rasin,7 Brian Gebelein,1 Matthew T. Weirauch,10
Nenad Sestan,4 John H. Martin,2,3 Yutaka Yoshida1*
Superior manual dexterity in higher primates emerged together with the appearance of
cortico-motoneuronal (CM) connections during the evolution of the mammalian
corticospinal (CS) system. Previously thought to be specific to higher primates, we
identified transient CM connections in early postnatal mice, which are eventually
eliminated by Sema6D-PlexA1 signaling. PlexA1 mutant mice maintain CM connections
into adulthood and exhibit superior manual dexterity as compared with that of controls.
Last, differing PlexA1 expression in layer 5 of the motor cortex, which is strong in wild-type
mice but weak in humans, may be explained by FEZF2-mediated cis-regulatory elements
that are found only in higher primates. Thus, species-dependent regulation of PlexA1
expression may have been crucial in the evolution of mammalian CS systems that
improved fine motor control in higher primates.
The emergence of sophisticated motor and cognitive abilities in humans has been ac- companied by complex central nervous ystem specializations. Axon trajectory and connectivity modifications contributed to
an advanced brain that enabled higher cogni-
tive functions and finer motor control (1). Species
differences in axonal trajectories, circuit connec-
tivity, and function are exemplified by the cor-
ticospinal (CS) tract (CST), which is essential for
voluntary movement. A key feature distinguish-
ing the CS systems of higher primates is hand
dexterity control. This dexterity likely arises from
the particular monosynaptic connections between
CS neurons and motor neurons (MNs) that con-
trol hand muscles in higher primates (2). In other
mammals, these cortico-motoneuronal (CM) con-
nections may fail to develop, or they may form
and then become actively eliminated. CS cir-
cuit pathways also differ substantially, with
CSTs in higher primates descending within the
ventral and lateral funiculi of the spinal cord,
and those in rodents descending in the dorsal
There are neither substantial contacts be-
tween CST axons and MNs nor functional CM
connections in adult rodents (3–6). To examine
early postnatal mice for CM connections, we per-
formed monosynaptic rabies virus tracing from
forelimb muscles at postnatal day 3 (P3) (Fig. 1A).
When motor cortices were analyzed for mCherry
expression 8 days after injection, we observed
mCherry+ CS neurons in both hemispheres with
more extensive contralateral labeling (Fig. 1, B
and D), providing evidence of CM connections
in juvenile mice.
We then labeled CST fibers genetically using
Emx1-Cre;cc-GFP mice and examined the post-
natal CST innervation patterns within the spinal
cord (fig. S1, A and C to M). In P2 mice, enhanced
green fluorescent protein–labeled (eGFP+) CST
axons were detected in the ventral-most re-
gion of the dorsal funiculus (dCST) at upper
cervical levels only (fig. S1, C to E). We also ob-
served eGFP+ CST fibers in the ventral and lat-
eral funiculi (vCST and lCST; together, vlCST) at
cervical, thoracic, and lumbar levels at P2 (fig.
S1, C to K and N, purple bars). The density of the
eGFP+ vlCST decreased at P10 and was unde-
tectable at P14 and later (fig. S1, B and L to N).
Unilateral injections of AAV1-hSyn-Cre into the
motor cortex of ccGFP mice at P4 led to vlCST
labeling in the ipsilateral spinal cord at P10 (fig.
S2, A to F). The vlCST constituted ~20% of all the
descending CSTs (fig. S2, G to J). Analysis of the
cervical spinal cords of P2 or P7 mice showed
that presynaptic terminals of the ipsilateral vlCST
or contralateral dCST form contacts on MNs
(fig. S2, K and L).
Next, we examined whether the semaphorin
(Sema) family of repulsive (or attractive) molecules
1Division of Developmental Biology, Cincinnati Children’s
Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA.
2Department of Cellular, Molecular, and Biomedical Sciences,
City University of New York School of Medicine, New York, NY
10031, USA. 3Graduate Center, City University of New York,
New York, NY 10017, USA. 4Department of Neuroscience,
Kavli Institute for Neuroscience, Yale School of Medicine, New
Haven, CT 06510, USA. 5Basic Medical School of Zhengzhou
University, Zhengzhou, Henan, 450001, P.R. China. 6Institute
for Personalized Medicine, Departments of Biochemistry
and Molecular Biology and Pharmacology, Penn State
College of Medicine, PA 17033, USA. 7Department
of Neuroscience and Cell Biology, Robert Wood Johnson
Medical School, Rutgers University, Piscatway, NJ 08854,
USA. 8Precursory Research for Embryonic Science
and Technology (PRESTO), Japan Science and Technology
Agency (JST), Kawaguchi, Saitama, 332-0012, Japan.
9Department of Respiratory Medicine and Clinical
Immunology, Graduate School of Medicine, Osaka University,
Suita, 565-0871, Japan. 10Center for Autoimmune Genomics
and Etiology, Division of Biomedical Informatics, and Division
of Developmental Biology, Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH 45229, USA.
*Corresponding author. Email: firstname.lastname@example.org
( Y. Y.); email@example.com (J.H. M.)