218:, which define features along the anterior-posterior axis of a developing organism, determine at which points along the axis that limb buds will form. Though limbs emerge at different locations in different species, their positions always correlate with the level of Hox gene expression along the anterior-posterior axis. All limb buds must also rely on other signaling factors to obtain their forelimb or hindlimb identity; Hox
639:
181:(ZPA) with the mesenchymal cells. These signaling centers are crucial to the proper formation of a limb that is correctly oriented with its corresponding axial polarity in the developing organism. Research has determined that the AER signaling region within the limb bud determines the proximal-distal axis formation of the limb using
873:
that are expressed throughout the developing hindlimb but not forelimb buds. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed
1405:
Ohuchi H, Nakagawa T, Yamamoto A, Araga A, Ohata T, Ishimaru Y, Yoshioka H, Kuwana T, Nohno T, Yamasaki M, Itoh N, Noji S (June 1997). "The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor".
399:; This experiment resulted in a duplication of limbs. Although excess retinoic acid can alter limb patterning by ectopically activating Shh expression, genetic studies in mouse that eliminate retinoic acid synthesis have shown that RA is not required for limb patterning.
141:
begin to proliferate to the point where they create a bulge under the ectodermal cells above. The mesoderm cells in the limb bud that come from the lateral plate mesoderm will eventually differentiate into the developing limb's connective tissues, such as
1317:
Ng JK, Kawakami Y, Büscher D, Raya A, Itoh T, Koth CM, Rodríguez
Esteban C, Rodríguez-León J, Garrity DM, Fishman MC, Izpisúa Belmonte JC (November 2002). "The limb identity gene Tbx5 promotes limb initiation by interacting with Wnt2b and Fgf10".
464:
initiate and regulate Hox gene expression in the developing limb bud. Though many of the finer details remain to be resolved, a number of significant connections between Hox gene expression and the impact on limb development have been discovered.
205:
that the dorsal ectoderm and ventral ectoderm use respectively. Because all of these signaling systems reciprocally sustain each other's activity, limb development is essentially autonomous after these signaling regions have been established.
128:
The limb bud consists of undifferentiated mesoderm cells that are sheathed in ectoderm. As a result of cell signaling interactions between the ectoderm and underlying mesoderm cells, formation of the developing limb bud occurs as
655:
These experiments reveal that the limb mesenchyme contains the necessary information concerning limb identity, but the AER is needed to stimulate the mesenchyme to live up to its destiny (of becoming an arm, leg, etc.)
686:
first specifies anterior-posterior polarity (and dictates digit identity), and then, by sustaining AER activity, it ensures that the necessary cell proliferation occurs for normal formation of a five-digit limb.
541:
expression. When beads were placed in the middle of the flank tissue, the anterior portion expressed Tbx5 and forelimb features, while the posterior portion of the limb expressed Tbx4 and hindlimb features.
548:(via viral-transfection) throughout their flank tissue, every limb they grew was a leg, even those that formed in the anterior region, which would normally become wings. This confirms the role of
1230:
Pizette S, Abate-Shen C, Niswander L (November 2001). "BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb".
1720:
Nelson CE, Morgan BA, Burke AC, Laufer E, DiMambro E, Murtaugh LC, Gonzales E, Tessarollo L, Parada LF, Tabin C (May 1996). "Analysis of Hox gene expression in the chick limb bud".
801:
Secreted by the ZPA in the limb bud mesenchyme. Creates concentration gradient that dictates formation of the five distinct digits. Digit 5 (pinkie) results from exposure to high
843:– Involved with the development of hindlimbs versus forelimbs. Though in chicks, they seem to be the primary factors involved in limb identity, in mice it appears that
1444:
Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua
Belmonte JC (April 1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity".
1916:
492:
is required, its effects change over time as the mesoderm is primed to respond to it differently. These three phases of regulation reveal a mechanism by which
880:– Responsible for dictating the anterior-posterior axis of an organism, and are intricately involved in patterning of the developing limb in conjunction with
765:– Secreted by the AER cells. Acts upon the mesenchymal cells, to maintain their proliferative state. Also induces the mesenchymal cells to secrete
593:) were turned on and drastic alterations of the muscles, bones, and tendons shifted the phenotype towards that of a hindlimb. This indicates that
296:(Shh). The ZPA also plays an important role in initially specifying digit identity, while later maintaining proper AER morphology and continued
292:(ZPA), in a small posterior portion of the limb bud helps to establish anterior-posterior polarity in the limb through secretion of the protein
925:
472:
expression can be divided up into three phases throughout limb bud development, which corresponds to three key boundaries in proximal-distal
1539:
Marcil A, Dumontier E, Chamberland M, Camper SA, Drouin J (January 2003). "Pitx1 and Pitx2 are required for development of hindlimb buds".
402:
367:
by FGF signaling which effects the primitive somitic mesoderm cells at different times depending on their axial location during organism
327:
genes that appears to be necessary for specification of the developing hindlimb, whereas their absence results in forelimb development.
711:
downregulation during limb bud expansion, the number of digits was decreased, but the identities of the formed digits was not altered.
1909:
950:
533:
and, subsequently, an entire limb. When the beads created limb buds towards the anterior region, forelimb formation coincided with
1179:
Parr BA, McMahon AP (March 1995). "Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb".
1500:"Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth"
1902:
1136:
Riddle RD, Johnson RL, Laufer E, Tabin C (December 1993). "Sonic hedgehog mediates the polarizing activity of the ZPA".
805:
concentrations, while digit 1 (thumb) on the opposite end of the spectrum develops in response to low concentrations of
78:
285:
loop between the limb mesenchymal cells and the AER maintains the continued growth and development of the entire limb.
1964:
692:
683:
627:
530:
481:
457:
449:
441:
289:
194:
186:
178:
122:
265:
expression in the above ectodermal cells – resulting in formation of the apical ectodermal ridge as well as inducing
202:
484:. The transition into the third phase is then marked by changes in how the limb bud mesenchymal cells responds to
73:
311:
specifies forelimb status. In mice, however, both hindlimbs and forelimbs can develop in the presence of either
1674:"Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth"
830:
826:
661:
648:
453:
234:
182:
61:
673:
When forelimb mesenchyme is replaced with non-limb mesenchyme, the AER regresses, and limb development halts.
529:
Placement of FGF10-containing beads beneath chick ectodermal cells results in the formation a limb bud, AER,
1959:
174:
1758:
Rodrigues AR, Yakushiji-Kaminatsui N, Atsuta Y, Andrey G, Schorderet P, Duboule D, Tabin CJ (March 2017).
134:
85:
37:
368:
230:
198:
440:
As previously stated, limb development is essentially autonomous after the signaling centers (AER) and
1672:
Sheth R, Grégoire D, Dumouchel A, Scotti M, Pham JM, Nemec S, Bastida MF, Ros MA, Kmita M (May 2013).
1942:
1453:
1188:
1051:
870:
355:
correlates with the time and place of expression. This statement is supported by the knowledge that
351:
are linked in four chromosomal clusters: Hoxa, Hoxb, Hoxc, and Hoxd. Their physical position on the
2000:
1353:
Kawakami Y, Capdevila J, Büscher D, Itoh T, Rodríguez
Esteban C, Izpisúa Belmonte JC (March 2001).
727:– Initially, Tbx proteins induce secretion of FGF10 by cells in the lateral plate mesoderm. Later,
169:
The limb bud remains active throughout much of limb development as it stimulates the creation and
1979:
1605:
1477:
1384:
1299:
1274:
Iimura T, Pourquié O (May 2007). "Hox genes in time and space during vertebrate body formation".
1212:
1161:
242:
1760:"Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells"
525:
can be initiated. Other signaling molecules are implicated in determining the limb's identity.
1881:
1842:
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1737:
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1556:
1521:
1469:
1423:
1376:
1335:
1291:
1247:
1204:
1153:
1118:
1077:
1040:"Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition"
1020:
946:
921:
784:
493:
364:
282:
170:
517:
FGF10 can induce limb formation, but T-box proteins, Pitx1, and Hox genes determine identity
448:
continue to participate in the dynamic regulation of limb development even after the AER and
125:
the upper limb bud appears in the third week and the lower limb bud appears four days later.
1947:
1873:
1861:
1832:
1822:
1781:
1771:
1729:
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1636:
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1239:
1196:
1145:
1108:
1067:
1059:
1010:
1002:
522:
473:
380:
110:
813:
expression has been shown in many, but not all circumstances, to be heavily connected with
476:. The transition from the first phase to the second phase is marked by the introduction of
250:
703:-null mutants) the AER morphology, particularly its anterior extent, is perturbed and its
219:
1355:"WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo"
1457:
1192:
1055:
647:
Mesenchymal cells determine limb identity, but the AER maintains limb outgrowth through
1837:
1811:"Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud"
1810:
1786:
1759:
1649:
1624:
1576:"Zebrafish limb development is triggered by a retinoic acid signal during gastrulation"
1072:
1039:
1015:
990:
881:
818:
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806:
802:
798:
708:
700:
631:
623:
611:
489:
485:
477:
461:
293:
229:
In turn, the activation of T-box protein activates signaling cascades that involve the
190:
1371:
1354:
1994:
1287:
1149:
619:
392:
372:
1625:"Mechanisms of retinoic acid signalling and its roles in organ and limb development"
1609:
1388:
1303:
892:) proteins. Determines where limb buds will form, and what limbs will develop there.
452:
have been established in the limb bud. Complex communication ensues as AER-secreted
1934:
1481:
1216:
1165:
396:
371:—and is even further specified with other anterior-posterior axis signals (such as
360:
245:
mesenchymal cells of the lateral plate mesoderm, which form the limb bud mesoderm.
1877:
300:
secretion – to ensure proper mitotic activity of the limb bud mesenchyme beneath.
1827:
1516:
1499:
855:
merely diverts a prospective forelimb from that path to become a hindlimb, or if
585:
was incorrectly expressed in mouse forelimbs, several hindlimb-associated genes (
417:) are expressed only in the anterior limbs in chickens, while the more 5’ genes (
66:
847:
is merely a downstream messenger enforcing the hindlimb-forming instructions of
670:
When forelimb mesenchyme is replaced with hindlimb mesenchyme, a hindlimb grows.
288:
In addition to limb outgrowth, the formation of a crucial signaling center, the
521:
By mimicking the initial FGF10 secretions of the lateral plate mesoderm cells,
1969:
732:
352:
274:
189:
signaling establishes the anterior-posterior axis formation of the limb using
159:
130:
107:
32:
1885:
193:. Additionally, though not known as a specific signaling region like AER and
1776:
1419:
1331:
1243:
1063:
877:
696:
445:
388:
376:
348:
347:
varies as a function of the position along the anterior-posterior axis. The
344:
197:, the dorsal-ventral axis is established in the limb bud by the competitive
143:
1846:
1795:
1733:
1699:
1658:
1601:
1560:
1525:
1473:
1380:
1339:
1295:
1251:
1113:
1096:
1081:
1024:
610:
HOXD11 is expressed posteriorly, near the ZPA, where the highest levels of
1741:
1427:
1208:
1157:
1122:
814:
755:
secretion, is involved in a positive feedback loop with the AER, through
571:
501:
497:
469:
406:
384:
356:
215:
118:
114:
91:
1974:
1809:
Zhu J, Nakamura E, Nguyen MT, Bao X, Akiyama H, Mackem S (April 2008).
1690:
1673:
1592:
1575:
822:
505:
163:
155:
138:
1894:
1862:"Role of Pitx1 Upstream of Tbx4 in Specification of Hindlimb Identity"
1552:
1006:
945:(3. ed.). Philadelphia, Pa.: Churchill Livingstone. p. 317.
865:– Responsible for the development of a hindlimb-associated phenotype.
1200:
590:
429:) are expressed only in the posterior limbs. The intermediate genes (
426:
422:
151:
121:, formation occurs roughly around the fourth week of development. In
1640:
664:-bead is added in the AER's place, normal limb development proceeds.
638:
991:"How the embryo makes a limb: determination, polarity and identity"
1465:
889:
885:
862:
852:
848:
788:
780:
770:
766:
752:
744:
740:
736:
728:
724:
637:
594:
582:
575:
564:
549:
434:
430:
418:
414:
410:
409:
expression in regard to limb development. The most 3’ Hoxc genes (
324:
320:
278:
258:
254:
246:
238:
223:
49:
1926:
1097:"The roles of FGFs in the early development of vertebrate limbs"
874:
into limbs with some morphological characteristics of hindlimbs.
866:
856:
844:
840:
836:
792:
774:
762:
756:
748:
704:
678:
ZPA's role in establishing polarity and further limb development
598:
586:
560:
556:
545:
538:
534:
335:
appear to be important specifically for limb outgrowth in mice.
332:
328:
316:
312:
308:
304:
297:
270:
266:
262:
147:
1898:
496:
can independently modify each of the three limb segments – the
444:) have been established. However, it is important to know that
437:) are expressed in both the upper and lower limbs in chickens.
277:
in a mitotically active state and sustains their production of
226:
that, in turn, determine limb identity for certain organisms.
544:
When chick embryos were engineered to constitutively express
339:
Relationship between hox gene expression and limb patterning
257:
expression in the forelimb and hindlimb, respectively. This
237:. Before limb development begins, T-box proteins initiate
859:
is activated by another Pitx1-like messenger, is unknown.
869:
is one of its downstream targets. Pitx1 and Tbx4 encode
787:
loop between the AER and limb mesenchyme. Activated by
660:
When the AER is removed, limb development halts. If an
606:
HOXD11 expression correlates with Shh signals secretion
273:
secreted by the AER acts to keep the cells of the limb
601:—plays a role in the emergence of hindlimb properties.
574:
pathway affects Tbx expression, which in turn affects
16:
Structure formed early in vertebrate limb development
1498:
Minguillon C, Del Buono J, Logan MP (January 2005).
537:
expression, while hindlimb formation coincided with
1933:
642:
Cutaneous innervation of the right upper extremity.
72:
60:
48:
43:
31:
26:
21:
833:activity, FGF expression in the AER is maintained.
154:. Moreover, the mesoderm cells that come from the
1860:Logan, Malcolm; Tabin, Clifford J. (1999-03-12).
567:expression in the lateral plate mesoderm in mice.
731:expression is restricted to the developing limb
1753:
1751:
1493:
1491:
1439:
1437:
1715:
1713:
1711:
1709:
1400:
1398:
1269:
1267:
1265:
1263:
1261:
405:is a wonderful example of this specificity of
1910:
984:
982:
8:
980:
978:
976:
974:
972:
970:
968:
966:
964:
962:
691:When Shh signals normally secreted from the
343:Within the limb bud, expression of specific
911:
909:
907:
905:
667:When an extra AER is added, two limbs form.
1917:
1903:
1895:
630:is transplanted, or ectopic expression of
113:. As a result of interactions between the
1836:
1826:
1785:
1775:
1689:
1648:
1591:
1515:
1370:
1112:
1071:
1014:
634:is stimulated, HOXD11 expression follows.
375:). Additional evidence for the role that
173:retention of two signaling regions: the
79:bud_by_E5.0.3.0.0.0.5 E5.0.3.0.0.0.5
901:
158:will eventually differentiate into the
1623:Cunningham, T.J.; Duester, G. (2015).
747:, which acts upon the AER and induces
89:
18:
735:, where it is stabilized by WNT8C or
695:are inhibited (either through use of
7:
751:expression. The mesenchyme, through
707:signaling decreased. As a result of
383:was found when researchers effected
773:to sustain the AER's expression of
123:the development of the human embryo
743:expression activates secretion of
552:in the type of limb that develops.
14:
307:specifies hindlimb status, while
1288:10.1111/j.1440-169X.2007.00928.x
1574:Grandel H, Brand M (May 2011).
1038:Gros J, Tabin CJ (March 2014).
359:expression is initiated during
106:is a structure formed early in
888:and FGF signals (and possibly
783:– Acts as a middle man in the
720:Associated molecules include:
1:
1878:10.1126/science.283.5408.1736
1372:10.1016/s0092-8674(01)00285-9
884:. Influences the activity of
1828:10.1016/j.devcel.2008.01.008
1764:Proc. Natl. Acad. Sci. U.S.A
1517:10.1016/j.devcel.2004.11.013
1150:10.1016/0092-8674(93)90626-2
829:(BMP) activity. By blocking
1965:Zone of polarizing activity
941:Larsen, William J. (2001).
716:Relevant genes and proteins
488:. This means that although
290:zone of polarizing activity
179:zone of polarizing activity
2017:
365:primitive somitic mesoderm
989:Tickle C (October 2015).
916:Scott F. Gilbert (2010).
222:influences expression of
84:
1629:Nat. Rev. Mol. Cell Biol
827:bone morphogenic protein
1960:Apical ectodermal ridge
1777:10.1073/pnas.1620767114
1420:10.1242/dev.124.11.2235
1332:10.1242/dev.129.22.5161
1244:10.1242/dev.128.22.4463
1095:Martin GR (June 1998).
1064:10.1126/science.1248228
175:apical ectodermal ridge
1734:10.1242/dev.122.5.1449
1114:10.1101/gad.12.11.1571
920:. Sinauer Associates.
791:expression, activates
643:
261:expression stimulates
210:Position and formation
135:lateral plate mesoderm
86:Anatomical terminology
38:lateral plate mesoderm
918:Developmental Biology
871:transcription factors
769:, which acts through
641:
622:is applied to induce
319:. In fact, it is the
231:Wnt signaling pathway
1943:Triradiate cartilage
512:Relevant experiments
1872:(5408): 1736–1739.
1458:1999Natur.398..814R
1193:1995Natur.374..350P
1056:2014Sci...343.1253G
403:Chicken development
1980:Septum transversum
1691:10.1242/dev.089409
1593:10.1002/dvdy.22461
1276:Dev. Growth Differ
644:
614:expression occur.
563:knockout prevents
241:expression in the
1988:
1987:
1770:(12): 3139–3144.
1553:10.1242/dev.00192
1007:10.1111/joa.12361
927:978-0-87893-564-2
785:positive feedback
494:natural selection
283:positive feedback
171:positive feedback
131:mesenchymal cells
100:
99:
95:
2008:
1948:Limb development
1919:
1912:
1905:
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1806:
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1314:
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1201:10.1038/374350a0
1176:
1170:
1169:
1133:
1127:
1126:
1116:
1092:
1086:
1085:
1075:
1050:(6176): 1253–6.
1035:
1029:
1028:
1018:
986:
957:
956:
943:Human embryology
938:
932:
931:
913:
523:limb development
474:limb development
381:limb development
269:expression. The
111:limb development
92:edit on Wikidata
55:gemmae membrorum
19:
2016:
2015:
2011:
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1991:
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1984:
1929:
1925:Development of
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1803:
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1617:
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1572:
1568:
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1537:
1533:
1497:
1496:
1489:
1452:(6730): 814–8.
1443:
1442:
1435:
1414:(11): 2235–44.
1404:
1403:
1396:
1352:
1351:
1347:
1326:(22): 5161–70.
1316:
1315:
1311:
1273:
1272:
1259:
1238:(22): 4463–74.
1229:
1228:
1224:
1187:(6520): 350–3.
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1177:
1173:
1135:
1134:
1130:
1107:(11): 1571–86.
1094:
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1089:
1037:
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1032:
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987:
960:
953:
940:
939:
935:
928:
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899:
718:
514:
468:The pattern of
387:expressions in
341:
253:stabilize this
220:gene expression
212:
117:and underlying
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12:
11:
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1728:(5): 1449–66.
1705:
1684:(10): 2130–8.
1664:
1635:(2): 110–123.
1615:
1586:(5): 1116–26.
1566:
1531:
1487:
1433:
1394:
1365:(6): 891–900.
1345:
1309:
1257:
1222:
1171:
1144:(7): 1401–16.
1128:
1087:
1030:
958:
951:
933:
926:
900:
898:
895:
894:
893:
886:T-box proteins
875:
860:
834:
799:Sonic hedgehog
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717:
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713:
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626:expression, a
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579:
568:
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550:T-box proteins
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519:
518:
513:
510:
340:
337:
294:Sonic hedgehog
224:T-box proteins
211:
208:
177:(AER) and the
160:myogenic cells
98:
97:
88:
82:
81:
76:
70:
69:
64:
58:
57:
52:
46:
45:
41:
40:
35:
29:
28:
24:
23:
15:
13:
10:
9:
6:
4:
3:
2:
2013:
2002:
1999:
1998:
1996:
1981:
1978:
1976:
1973:
1971:
1968:
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1963:
1961:
1958:
1954:
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1950:
1949:
1946:
1944:
1941:
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1932:
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1915:
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1900:
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1875:
1871:
1867:
1863:
1856:
1853:
1848:
1844:
1839:
1834:
1829:
1824:
1821:(4): 624–32.
1820:
1816:
1812:
1805:
1802:
1797:
1793:
1788:
1783:
1778:
1773:
1769:
1765:
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1471:
1467:
1466:10.1038/19769
1463:
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1329:
1325:
1321:
1313:
1310:
1305:
1301:
1297:
1293:
1289:
1285:
1282:(4): 265–75.
1281:
1277:
1270:
1268:
1266:
1264:
1262:
1258:
1253:
1249:
1245:
1241:
1237:
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1053:
1049:
1045:
1041:
1034:
1031:
1026:
1022:
1017:
1012:
1008:
1004:
1001:(4): 418–30.
1000:
996:
992:
985:
983:
981:
979:
977:
975:
973:
971:
969:
967:
965:
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952:0-443-06583-7
948:
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868:
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835:
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828:
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797:
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764:
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746:
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734:
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723:
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721:
715:
710:
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677:
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672:
669:
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663:
659:
658:
657:
650:
646:
645:
640:
633:
632:Shh signaling
629:
625:
621:
620:retinoic acid
617:
616:
615:
613:
605:
604:
600:
596:
592:
588:
584:
580:
577:
573:
569:
566:
562:
558:
555:Knocking out
554:
551:
547:
543:
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536:
532:
528:
527:
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516:
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509:
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490:Shh signaling
487:
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443:
438:
436:
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394:
393:retinoic acid
390:
386:
382:
378:
374:
373:retinoic acid
370:
366:
362:
358:
354:
350:
346:
338:
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330:
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318:
314:
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306:
303:In chickens,
301:
299:
295:
291:
286:
284:
280:
276:
272:
268:
264:
260:
256:
252:
248:
244:
243:proliferating
240:
236:
232:
227:
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221:
217:
209:
207:
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200:
196:
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184:
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93:
87:
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68:
65:
63:
59:
56:
53:
51:
47:
42:
39:
36:
34:
30:
25:
20:
1952:
1935:Ossification
1869:
1865:
1855:
1818:
1814:
1804:
1767:
1763:
1725:
1721:
1681:
1677:
1667:
1632:
1628:
1618:
1583:
1579:
1569:
1547:(1): 45–55.
1544:
1540:
1534:
1510:(1): 75–84.
1507:
1503:
1449:
1445:
1411:
1407:
1362:
1358:
1348:
1323:
1319:
1312:
1279:
1275:
1235:
1231:
1225:
1184:
1180:
1174:
1141:
1137:
1131:
1104:
1100:
1090:
1047:
1043:
1033:
998:
994:
942:
936:
917:
817:expression.
719:
681:
654:
609:
520:
467:
439:
401:
397:gastrulation
361:gastrulation
342:
302:
287:
228:
213:
168:
162:of the limb
127:
103:
101:
54:
1722:Development
1678:Development
1541:Development
1408:Development
1320:Development
1232:Development
795:expression.
578:expression.
486:Shh signals
478:Shh signals
462:Shh signals
454:FGF signals
369:development
235:FGF signals
203:BMP signals
191:Shh signals
183:FGF signals
44:Identifiers
2001:Embryology
1970:Sclerotome
897:References
851:. Whether
821:also (via
759:secretion.
733:mesenchyme
649:FGF signal
624:Shh signal
612:Shh signal
504:, and the
460:-secreted
391:by adding
353:chromosome
275:mesenchyme
108:vertebrate
1886:0036-8075
1815:Dev. Cell
1504:Dev. Cell
1101:Genes Dev
878:Hox genes
825:) blocks
697:tamoxifen
651:secretion
597:—through
480:from the
446:Hox genes
389:zebrafish
377:Hox genes
349:Hox genes
345:Hox genes
216:Hox genes
144:cartilage
133:from the
33:Precursor
1995:Category
1953:Limb bud
1847:18410737
1796:28270602
1700:23633510
1659:25560970
1610:12858721
1602:21509893
1580:Dev. Dyn
1561:12441290
1526:15621531
1474:10235264
1389:17613595
1381:11290326
1340:12399308
1304:38557151
1296:17501904
1252:11714672
1082:24626928
1025:26249743
815:Hox gene
502:zeugopod
498:stylopod
470:Hox gene
407:Hox gene
385:Hox gene
379:play in
357:Hox gene
119:mesoderm
115:ectoderm
104:limb bud
22:Limb bud
1975:Myotome
1866:Science
1838:8284562
1787:5373353
1742:8625833
1650:4636111
1482:4330287
1454:Bibcode
1428:9187149
1217:4254409
1209:7885472
1189:Bibcode
1166:4973500
1158:8269518
1123:9620845
1073:4097009
1052:Bibcode
1044:Science
1016:4580101
995:J. Anat
823:Gremlin
506:autopod
395:during
164:muscles
156:somites
139:somites
67:D018878
27:Details
1884:
1845:
1835:
1794:
1784:
1740:
1698:
1657:
1647:
1608:
1600:
1559:
1524:
1480:
1472:
1446:Nature
1426:
1387:
1379:
1338:
1302:
1294:
1250:
1215:
1207:
1181:Nature
1164:
1156:
1121:
1080:
1070:
1023:
1013:
949:
924:
591:HOXC10
500:, the
427:HOXC11
423:HOXC10
152:tendon
150:, and
1606:S2CID
1478:S2CID
1385:S2CID
1300:S2CID
1213:S2CID
1162:S2CID
890:Pitx1
863:Pitx1
853:Pitx1
849:Pitx1
789:FGF10
781:WNT3A
771:WNT3A
767:FGF10
753:FGF10
745:WNT3A
741:FGF10
737:WNT2B
729:FGF10
725:FGF10
618:When
595:Pitx1
583:Pitx1
581:When
576:FGF10
565:FGF10
435:HOXC8
431:HOXC6
419:HOXC9
415:HOXC5
411:HOXC4
325:Pitx2
321:Pitx1
279:FGF10
259:FGF10
255:FGF10
251:WNT8C
247:WNT2B
239:FGF10
199:Wnt7a
90:[
50:Latin
1927:bone
1882:ISSN
1843:PMID
1792:PMID
1738:PMID
1696:PMID
1655:PMID
1598:PMID
1557:PMID
1522:PMID
1470:PMID
1424:PMID
1377:PMID
1359:Cell
1336:PMID
1292:PMID
1248:PMID
1205:PMID
1154:PMID
1138:Cell
1119:PMID
1078:PMID
1021:PMID
947:ISBN
922:ISBN
867:Tbx4
857:Tbx5
845:Tbx4
841:Tbx5
837:Tbx4
793:FGF8
775:FGF8
763:FGF8
757:FGF8
749:FGF8
705:FGF8
682:The
599:Tbx4
587:Tbx4
570:The
561:Tbx5
557:Tbx4
546:Tbx4
539:Tbx4
535:Tbx5
456:and
333:Tbx5
331:and
329:Tbx4
323:and
317:Tbx5
313:Tbx4
309:Tbx5
305:Tbx4
298:FGF8
271:FGF8
267:FGF8
263:WNT3
249:and
233:and
214:The
201:and
148:bone
137:and
102:The
62:MeSH
1874:doi
1870:283
1833:PMC
1823:doi
1782:PMC
1772:doi
1768:114
1730:doi
1726:122
1686:doi
1682:140
1645:PMC
1637:doi
1588:doi
1584:240
1549:doi
1545:130
1512:doi
1462:doi
1450:398
1416:doi
1412:124
1367:doi
1363:104
1328:doi
1324:129
1284:doi
1240:doi
1236:128
1197:doi
1185:374
1146:doi
1109:doi
1068:PMC
1060:doi
1048:343
1011:PMC
1003:doi
999:227
882:Shh
831:BMP
819:Shh
811:Shh
807:Shh
803:Shh
709:Shh
701:Shh
699:or
693:ZPA
684:ZPA
662:FGF
628:ZPA
572:Hox
559:or
531:ZPA
482:ZPA
458:ZPA
450:ZPA
442:ZPA
363:in
315:or
281:.
195:ZPA
187:ZPA
1997::
1880:.
1868:.
1864:.
1841:.
1831:.
1819:14
1817:.
1813:.
1790:.
1780:.
1766:.
1762:.
1750:^
1736:.
1724:.
1708:^
1694:.
1680:.
1676:.
1653:.
1643:.
1633:16
1631:.
1627:.
1604:.
1596:.
1582:.
1578:.
1555:.
1543:.
1520:.
1506:.
1502:.
1490:^
1476:.
1468:.
1460:.
1448:.
1436:^
1422:.
1410:.
1397:^
1383:.
1375:.
1361:.
1357:.
1334:.
1322:.
1298:.
1290:.
1280:49
1278:.
1260:^
1246:.
1234:.
1211:.
1203:.
1195:.
1183:.
1160:.
1152:.
1142:75
1140:.
1117:.
1105:12
1103:.
1099:.
1076:.
1066:.
1058:.
1046:.
1042:.
1019:.
1009:.
997:.
993:.
961:^
904:^
839:,
809:.
739:.
589:,
508:.
433:,
425:,
421:,
413:,
185:.
166:.
146:,
74:TE
1918:e
1911:t
1904:v
1888:.
1876::
1849:.
1825::
1798:.
1774::
1744:.
1732::
1702:.
1688::
1661:.
1639::
1612:.
1590::
1563:.
1551::
1528:.
1514::
1508:8
1484:.
1464::
1456::
1430:.
1418::
1391:.
1369::
1342:.
1330::
1306:.
1286::
1254:.
1242::
1219:.
1199::
1191::
1168:.
1148::
1125:.
1111::
1084:.
1062::
1054::
1027:.
1005::
955:.
930:.
777:.
94:]
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