(发育生物学）VI 胚层发育与器官系统发生（II）

1、( (发育生物学）发育生物学）VI VI 胚层发育与器官胚层发育与器官系统发生（系统发生（IIII）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 axes 3

2、.6 Development of the digits Development of the 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

3、 three axes 3.6 Development of the digits Development of the vertebrate limbThe vertebrate limb develops from a limb budAER: apical ectodermal ridgeProliferation of mesodermal cells from the lateral plate mesoderm causes the limb bud to bulge outwardLimb budEctodermal tissue: the outer layerCells fr

4、om the lateral plate mesoderm: skeletal elementsCells from the somites: the limbs musculature FGF10 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

5、 beneath the flank ectoderm induces extra limbFGF10Ectopic limbKnock-out of FGF10 in the mouse embryo results in embryos lacking the limb budFGF10 initiates the limb bud-forming interactions between the ectoderm and the mesoderm via dual signaling inductionA: FGF10 is originally expressed throughout

6、 the lateral plate mesodermB: FGF10 becomes restricted to the limb bud-forming regions, controlled by Wnt 2b and Wnt 8c respectively (via modulating FGF10 protein stability)C: Dual induction between FGF10 in the mesoderm and FGF8 in the apical ectoderm ridge to maintain the mesenchyme cells in the l

7、imb bud proliferating.Molecular model for the initiation of the limb bud in the chick between 48 and 54 hours of gestationLimb bud formation: the mesenchyme cells from lateral plate mesoderm proliferate to accumulate under the ectodermal tissue for forming a circular bulge3 The limb development3.1 S

8、pecification 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 vertebrate limbAER: Apical ec

9、todermal ridge PZ: Progress zone The AER is required for both the outgrowth of limb and the correct proximo-distal patterningFGF8 is expressed in the apical ectodermal ridge (AER)FGF8 can functionally substitute for the AERThe AER: a major signaling center for the developing limb, and maintains the

10、mesenchyme in a proliferating phase that enables the Pr-D growth of the limbThe mesenchyme cells: induce and sustain the AER, and determine the type of limb to be formed.The proximal-distal growth of the limb bud involves interactions between the AER and the underlying mesenchyme n Role of the AER o

11、r the PZ (progress zone) in specifying 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 ?An early wing-bud progress zone was transplanted to a later wing bud A late wing

12、-bud progress zone was transplanted to an early wing budExtra proximal structureLack of intermediate structures (digits emerge from the humerus without an intervening ulna/radius)Specification of proximal-distal axis is controlled by the progress zone mesenchyme, rather the AER (I) The following two

13、 transplantation experiments indicate that the PZ controls the specification of the proxiomal-distal axis of the developing limbs Specification of proximal-distal axis is controlled by the progress zone mesenchyme, rather the AER (I)Older AER combined with younger mesoderm generates normal limbs, ra

14、ther than producing limbs with deletions in the middle.Younger AER combined with older mesoderm generates normal limbs, rather than producing duplications of structures. The following two transplantation experiments do not support the notion that the AER specifies the proxiomal-distal axis of the de

15、veloping limbs 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: predetermination in early budHox genes specify the Pr-D axis of the limb Hox genes specify the Pr-D

16、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 for a mutation at the Hoxd-13 lociA: Wild-type mo

17、use forelimbB: Forelimb of mouse doubly mutant for Hoxa-11 and Hoxd-113 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 Coordinat

18、ing the three axes 3.6 Development 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

19、those of the Spemann organizer in amphibiansSonic hedgehog (Shh) is expressed in the ZPAShhShhSonic hedgehog (Shh) defines the signaling activity of the ZPA for development of the AP axisSonic hedgehog (Shh) forms a morphogen (signaling) gradient that specifies pattern along the limbs anterior-poste

20、rior axisThe molecular basis for specification of ZPAFGF8 in the AER induces the mesenchyme expressing the transcription factors Hoxb-8 and dHAND in the posterior region of limb bud to express Shh, thereby forming the ZPA3 The limb development3.1 Specification and formation of the limb bud3.2 The li

21、mb 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 limbThe dorsal-ventral polarity of the limb bud is determined by the o

22、verlying ectodermn If the ectoderm is rotated 180 with respect to the limb bud mesenchyme, the dorsal-ventral axis is partially reversed n The Wnt7a gene is specifically expressed in the dorsal ectoderm (but not ventral ) of chick and mouse limb buds, suggesting a role of Wnt7a in specifying dorsal-

23、ventral polarityLoss of Wnt7a function leads to disruption 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 genedorsalventralThe molecular mechanisms underlying the Wnt7a-med

24、iated DV patterning of the limbWnt7a in the dorsal ectodermLmx1 (a transcription factor) in the dorsal mesodermSpecify the dorsal cell fates in the 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 anteri

25、or-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 coordinate limb growth and patterning along the three limb axes In many Wnt 7a mutant mice, posterior digits are lacking, suggesting that Wnt 7a is also required for normal antero-posterior patterning3 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-posteri