(Fig. 4) supports the hypothesis that the integumentary structures in Ornithischia, already
described in Psittacosaurus (12) and Tianyulong
(13), could be homologous to the “protofeathers”
in non-avian theropods. In any case, it indicates
that those protofeather-like structures were
probably widespread in Dinosauria, possibly even
in the earliest members of the clade. Further,
the ability to form simple monofilaments and
more complex compound structures is potentially
nested within the archosauromorph clade, as exemplified by Longisquama (23), pterosaurs (24),
ornithischians, and theropods (including birds).
In Kulindadromeus and most ornithuromorph
birds (17, 25), the distal hindlimb is extensively
covered by scales and devoid of featherlike
structures. This condition might thus be primitive in dinosaurs. Both paleontological and genetic evidence, however, suggests that the pedal
scales of ornithuromorph birds are secondarily
derived from feathers. In avialan evolution, leg
feathers were reduced gradually in a distal-to-proximal direction, with eventual loss of the distal feathers and appearance of pedal scales in
ornithuromorphs (25). Further, evo-devo experiments (26, 27) show that feathers in extant
birds are the default fate of the avian epidermis,
and that the formation of avian scales requires
the inhibition of feather development. The local
formation of scales requires the inhibition of
epidermal outgrowth, regulated by the sonic
hedgehog pathway; this inhibition is partially
lost in the case of breeds with feathered feet
(27). Therefore, it is possible that the extensively scaled distal hindlimbs in Kulindadromeus
might be explained by similar local and partial
inhibition in the development of featherlike
structures. The preservation of featherlike structures and scales in the basal neornithischian
Kulindadromeus, and their similarity to structures that are present in diverse theropods and
ornithuromorph birds, thus strongly suggest
that deep homology mechanisms (28) explain
the complex distribution of skin appendages
within dinosaurs (23).
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We thank A. B. Ptitsyn for making fossils available for study;
Ph. Claeys, J.-M. Baele, and I. Y. Bolosky for help and comments
on the manuscript; and P. Golinvaux, J. Dos Remedios Esteves,
C. Desmedt, and A. Vandersypen for the drawings and
reconstructions. This study was supported by Belgian Science
Policy grant BL/36/62 to P.G. and by Natural Environment
Research Council Standard Grant NE/I027630/1 awarded to M.J.B.
Materials and Methods
Figs. S1 to S11
13 March 2014; accepted 23 June 2014
Ribosome stalling induced by
mutation of a CNS-specific tRNA
Ryuta Ishimura,1 Gabor Nagy,1 Ivan Dotu,2 Huihao Zhou,3
Xiang-Lei Yang,3 Paul Schimmel,3 Satoru Senju,4 Yasuharu Nishimura,4
Jeffrey H. Chuang,2 Susan L. Ackerman1†
In higher eukaryotes, transfer RNAs (tRNAs) with the same anticodon are encoded by
multiple nuclear genes, and little is known about how mutations in these genes affect
translation and cellular homeostasis. Similarly, the surveillance systems that respond to
such defects in higher eukaryotes are not clear. Here, we discover that loss of GTPBP2, a
novel binding partner of the ribosome recycling protein Pelota, in mice with a mutation in a
tRNA gene that is specifically expressed in the central nervous system causes ribosome
stalling and widespread neurodegeneration. Our results not only define GTPBP2 as a
ribosome rescue factor but also unmask the disease potential of mutations in nuclear-encoded tRNA genes.
In higher eukaryotes, the nuclear genome typically contains several hundred transfer RNA(tRNA) genes, which fall into isoaccep- tor groups, each representing an anticodon (1). Relative to the total number of tRNA
genes, the number of isodecoders—i.e., tRNA
molecules with the same anticodon but differ-
ences in the tRNA body—increases dramatically
with organismal complexity, which leads to spec-
ulation that isodecoders might not be fully re-
dundant with one another (2). Overexpression of
reporter constructs with rare codons that are
decoded by correspondingly low-abundance tRNAs
in bacteria and yeast, or mutations in single-copy
mitochondrial tRNA genes, may result in stalled
elongation complexes (3–5). However, the con-
sequences of mutations in multicopy, nuclear-
encoded tRNA isodecoder genes or in the
surveillance systems that eliminate the effect
of such tRNA mutations are not known in higher
The nmf205 mutation was identified in an
N-ethyl-N-nitorosurea mutagenesis screen of
C57BL/6J (B6J) mice for neurological phenotypes (6). B6J-nmf205–/– mice were indistinguishable from wild-type mice at 3 weeks of age but
showed clear truncal ataxia at 6 weeks (movie
S1). Mice died at 8 to 9 weeks with severe locomotor deficits. Progressive apoptosis of neurons
in the inner granule layer (IGL) in the mutant
cerebellum was initially observed between 3 and
4 weeks of age (Fig. 1, A to H). Apoptosis of
mutant granule cells in the dentate gyrus, CA2
pyramidal neurons, and layer IV cortical neurons
occurred between 5 and 8 weeks of age (Fig. 1, I
and J, and fig. S1, A to H). Further, many neurons
in the retina—including photoreceptors and ama-crine, horizontal, and ganglion cells—degenerated
during this time (Fig. 1, K and L, and fig. S1, I to T).
sciencemag.org 25 JULY 2014 • VOL 345 ISSUE 6195 455
1Howard Hughes Medical Institute and The Jackson Laboratory,
600 Main Street, Bar Harbor, ME 04609, USA. 2The Jackson
Laboratory for Genomic Medicine, 263 Farmington Avenue,
Farmington, CT 06030, USA. 3The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey
Pines Road, La Jolla, CA 92037, USA. 4Department of
Immunogenetics, Graduate School of Medical Sciences,
Kumamoto University, Honjo 1-1-1, Chuo-ku, Kumamoto
*These authors contributed equally to this work. †Corresponding
author. E-mail: email@example.com
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