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1、Cell, Vol. 101, 435445, May 12, 2000, Copyright 2000 by Cell PressA Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural TubeThe secretion of Shh by the notochord and floor plate controls the specification of ventral cell types (Marti et al.,1995;Roelin
2、ketal.,1995;Chiangetal.,1996;Ericson et al., 1996). Five distinct classes of ventral neurons can be generated in vitro in response to progressive 2- toJames Briscoe,* Alessandra Pierani,* Thomas M. Jessell,*and Johan Ericson* *Howard Hughes Medical Institute Department of Biochemistry and Molecular
3、Biophysics Columbia University 3-fold changes in extracellular Shh concentration (Eric-New York, New York 10032 sonetal.,1997a,1997b).Moreover,thepositionatwhichDepartment of Cell and Molecular Biology each of these neuronal classes is generated in vivo isMedical Nobel Institute predicted by the con
4、centration of Shh required for theirKarolinska Institute induction in vitro: neurons generated in progressivelyS 17177 Stockholm more ventral regions of the neural tube require corre-Sweden spondingly higher concentrations of Shh for their induc- tion (Ericson et al., 1997a). These observations have
5、 led to the view that the position that ventral progenitor cellsSummary occupy within a ventral-to-dorsal gradient of extracellu- lar Shh activity directs their differentiation into specificDistinct classes of neurons are generated at defined neuronal subtypes (Ericson et al., 1997b).positions in th
6、e ventral neural tube in response to a In turn, these findings have focused attention on thegradient of Sonic Hedgehog (Shh) activity. A set of steps by which graded Shh signaling directs the diversi-homeodomaintranscriptionfactorsexpressedbyneu-ficationofneuralprogenitorcells.Severalhomeodomainralp
7、rogenitorsactasintermediariesinShh-dependentproteins, Pax7, Pax3, Pax6, Dbx1, Dbx2, and Nkx2.2 areneural patterning. These homeodomain factors fallexpressed by ventral progenitor cells and their expres-into two classes: class I proteins are repressed by Shhsion is regulated by Shh signaling (Gouldin
8、g et al., 1993;and class II proteins require Shh signaling for theirEricsonetal.,1996,1997a;Briscoeetal.,1999;Pieranietexpression. The profile of class I and class II proteinal., 1999) Moreover, the pattern of generation of certainexpression defines five progenitor domains, each ofventral neuronal s
9、ubtypes is perturbed in mice carryingwhich generates a distinct class of postmitotic neu-mutations in these Pax genes and in the Nkx2.2 generons. Cross-repressive interactions between class I(Ericson et al., 1997a; Mansouri and Gruss, 1998;and class II proteins appear to refine and maintainBriscoe e
10、t al., 1999), supporting the view that homeodo-these progenitor domains. The combinatorial expres-main proteins expressed by ventral progenitor cells reg-sion of three of these proteinsNkx6.1, Nkx2.2, andulateneuronalsubtypeidentity.However,twoimportantIrx3specifies the identity of three classes of
11、neuronsaspects of the link between Shh signaling and neuronalgenerated in the ventral third of the neural tube.identity remain obscure. First, it is unclear how the pre- sumed extracellular gradient of Shh activity results inIntroductionstableandsharplydelineateddomainsofhomeodomain protein expressi
12、on within ventral progenitor cells. Sec-In many developing tissues, the generation of distinctond, the spatial information provided by the homeodo-celltypesisinitiatedbytheactionofextracellularsignalsmain proteins characterized to date is insufficient toprovided by local organizing centers. Certain
13、signalsexplain the diversity of neuronal subtypes generated athave the additional feature of directing distinct cell fatesdifferent dorsoventral positions.at different threshold concentrations, and thus functionIn this paper we address these two issues. We showas morphogens (Wolpert, 1969). In Droso
14、phila, the pat-first that the homeodomain proteins Nkx6.1 and Irx3 areterning of embryonic segments and imaginal discs in-expressed by progenitor cells in discrete domains ofvolves the graded signaling activities of the Hedgehog,the ventral neural tube and are regulated by graded Shh Wingless, and T
15、GFb-related proteins (Lawrence andsignaling. Thedifferential expression of fiveclass I (Shh- Struhl, 1996). In vertebrate embryos, the specificationrepressed) proteins, Pax7, Irx3, Dbx1, Dbx2, and Pax6, of mesodermal cell types has similarly been suggestedand two class II (Shh-induced) proteins, Nkx
16、6.1 and to depend on the graded signaling activity of membersNkx2.2, subdivides the ventral neural tube into five of the TGFb family (Smith, 1995; McDowell and Gurdon,cardinal progenitor domains. By misexpressing individ- 1999).Thegenerationofcellpatternthroughmorphogenual proteins in the neural tube in vivo, we provide evi- signaling demands an effective means of convertingdence that cross-repressive interactions between class graded extracellular activities into all-or-none distinc-I an
