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1、Developmental BiologyChapter 6: Organogenesis development of the vertebrate limbThe embryonic chick wingThe vertebrate limb development is a particularly good system in which to study pattern formation during organogenesis (I)n The vertebrate limb is a complex organ with three developmental axes: th
2、e proximo-distal axis running from the base of the limb to the tip, the antero-posterior axis running parallel with the body AP axis, and the dorso-ventral axis running from the back of the hand to the palm.Thus, the limb development is a particularly good system in which to study pattern formationn
3、Since the limbs, unlike heart or brain, are not essential for embryonic life, one can experimentally remove or transplant parts of the developing limb, or create limb-specific mutants without interfering with the vital processes of the organism. This is good advantage of studying pattern formation i
4、n organogenesisThe vertebrate limb development is a particularly good system in which to study pattern formation during organogenesis (II)n The limb is a good model for studying cellular interactions within a structure containing a large number of cells, and for elucidating the role of intercellular
5、 signaling in development. Recently, particular signal proteins have been identified to function in patterning along each of three limb axes:FGF family in Pr-D axial patterningSonic hedgehog (Shh) protein in A-P axial patterningWnt7a in D-V axial patterning The vertebrate limb develops from a limb b
6、ud3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits Development of the
7、vertebrate limb3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits Develo
8、pment of the vertebrate limbThe vertebrate limb develops from a limb budProliferation of mesodermal cells from the lateral plate mesoderm causes the limb bud to bulge outwardWhile the lateral plate mesodermal cells generate the skeletal elements of the limb, cells from the somites provide the limbs
9、musculatureFGF10 secreted from the lateral plate mesoderm cells is the signal for limb bud inductionA: FGF10 becomes expressed in the lateral plate mesoderm of the limb bud-forming regionB: Ectopic expression of FGF10 beneath the flank ectoderm induces extra limbFGF10Ectopic limbFGF10 initiates the
10、limb bud-forming interactions between the ectoderm and the mesoderm via dual signaling inductionA: FGF10 is originally expressed throughout the lateral plate mesodermB: FGF10 becomes restricted to the limb bud-forming regions, controlled by Wnt 2b and Wnt 8c respectivelyC: Dual induction between FGF
11、10 in the mesoderm and FGF8 in the apical ectoderm ridge (AER)Molecular model for the initiation of the limb bud in the chick between 48 and 54 hours of gestation3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3
12、The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits Development of the vertebrate limbApical ectodermal ridge (AER)Progress zone (PZ)The AER is required for both the outgrowth of limb and the correct proximo-dis
13、tal patterningFGF8 is expressed in the apical ectodermal ridge (AER)FGF8 can functionally substitute for the AERThesimilarresultscanbeobtainedwithFGF4,indicatingthatFGF8/FGF4arekeysignalsfortheAERThe mesenchyme cells:induce and sustain the AER, and determine the type of limb to be formed.The AER:a m
14、ajor signaling center for the developing limb, and maintains the mesenchyme in a proliferating phase that enables the Pr-D growth of the limbThe proximal-distal growth of the limb bud involves interactions between the AER and the underlying mesenchyme n Role of the AER or the PZ (progress zone) in s
15、pecifying the proximal-distal axis?n The mechamisms underlying the PD axis specification and patterning?How is development of the proximal-distal axis accomplished during the limb outgrowth ?Specification of proximal-distal axis is controlled by the progress zone mesenchyme, rather the AER (I)A.Olde
16、r AER combined with younger mesoderm generates normal limbs, rather producing limbs with deletions in the middle.B.Younger AER combined with older mesoderm generates normal limbs, rather producing duplications of structures. The following two transplantation experiments did not support the notion th
17、at the AER specifies the proxiomal-distal axis of the developing limbs. A.An early wing-bud progress zone was transplanted to a late wing bud that had alrealy formed ulna and radiusB.A late wing-bud progress zone was transplanted to an early wing budExtra proximal structureLack of intermediate struc
18、turesSpecification of proximal-distal axis is controlled by the progress zone mesenchyme, rather the AER (II)Two proposed models for the mesodermal specification of the Pr-D axis of the limb a: the timing mechanism, the cell fate being determined by how long they remain in the progress zoneb: predet
19、ermination in early budHox genes specify the Pr-D axis of the limb Hox genes specify the Pr-D axis of the limb Loss of function mutations in Hoxa-11 and Hoxd-11 lead to lacking the ulna and radius of the forelimbs Human synpolydactyly (many fingers joined together) syndrome results from homozygosity
20、 for a mutation at the Hoxd-13 loci3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development
21、of the digits Development of the vertebrate limbZone of polarizing activity (ZPA) can specify the limb pattern along the anterior-posterior axisThe zone of polarizing activity (ZPA) in the posterior limb bud has organizing properties that are almost as striking as those of the Spemann organizer in a
22、mphibiansSonic hedgehog (Shh) is expressed in the ZPAShhShhSonic hedgehog defines the signaling activity of the ZPA for development of the AP axisThe molecular basis for specification of ZPAFGF8 in the AER induces the mesenchyme expressing the transcription factors Hoxb-8 and dHAND to express Shh ,
23、thereby forming the ZPA in the posterior region of limb budSonic hedgehog forms a morphogen gradient that specifies pattern along the limbs anterior-posterior axis3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3
24、 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits Development of the vertebrate limbThe dorsal-ventral polarity of the limb bud is determined by the ectoderm encasing itnIf the ectoderm is rotated 180 with re
25、spect to the limb bud mesenchyme, the dorsal-ventral axis is partially reversed. nThe Wnt7a gene is specifically expressed in the dorsal (but not ventral ) ectoderm of chick and mouse limb buds, suggesting a role of Wnt7a in specifying dorsal-ventral polarity. Loss of Wnt7a function leads to disrupt
26、ion of the dorsal-ventral patterning of the limbVt: the ventral tendons（肌腱肌腱）Vp: the ventral footpad（脚垫脚垫）A: Wild type embryonic mouse forelimb pawB: The mice deficient for Wnt7a geneThe molecular mechanisms underlying the Wnt7a-mediated DV patterning of the limbWnt7a induces activation of the Lmx1
27、gene in the dorsal mesenchyme. Lmx1 gene encodes a transcription factor that appears to be essential for specifying dorsal cell fates in the limbSpatial expression of Wnt7a in the dorsal ectoderm is regulated by engrailed gene in the ventral ectoderm.3 The limb development3.1 Specification and forma
28、tion of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three axes 3.6 Development of the digits Development of the vertebrate limbMolecular interactions that coordina
29、te limb growth and patterning along the three limb axes 3 The limb development3.1 Specification and formation of the limb bud3.2 The limb outgrowth and generation of the proximal-distal axis3.3 The anterior-posterior axial patterning 3.4 Patterning the dorsal-ventral axis 3.5 Coordinating the three
30、axes 3.6 Development of the digits Development of the vertebrate limbThe interdigital tissue specifies the identity of the digit forming anteriorly to the interdigital region in chick feetThe digital identity is regulated by BMP signaling in the interdigital regionApplication of the BMP inhibitor No
31、ggin to the interdigital regions causes alterations in the digital identity similar to those observed when the interdigital region is removedSeparation of the digits is the result of programmed cell deathRegulation of the limb apoptosis by BMPsGremlin: an inhibitor of BMPsInhibition of cell death in the interdigital regions by blocking BMP signaling leads to the webbing of chick feet
