Developmental mechanisms directing early anterior forebrain specification in vertebrates

Abstract

Research from the last 15 years has provided a working model for how the anterior forebrain is induced and specified during the early stages of embryogenesis. This model relies on three basic processes: (1) induction of the neural plate from naive ectoderm requires the inhibition of BMP/TGFβ signaling; (2) induced neural tissue initially acquires an anterior identity (i.e., anterior forebrain); (3) maintenance and expansion of the anterior forebrain depends on the antagonism of posteriorizing signals that would otherwise transform this tissue into posterior neural fates. In this review, we present a historical perspective examining some of the significant experiments that have helped to delineate this molecular model. In addition, we discuss the function of the relevant tissues that act prior to and during gastrulation to ensure proper anterior forebrain formation. Finally, we elaborate data, mainly obtained from the analyses of mouse mutants, supporting a role for transcriptional repressors in the regulation of cell competence within the anterior forebrain. The aim of this review is to provide the reader with a general overview of the signals as well as the signaling centers that control the development of the anterior neural plate.

Fig. 1

Dorsal blastopore lip tissue of the early gastrula displays organizing activity. Excision of dorsal blastopore lip tissue from the pigmented newt Triturus taeniatus and transplantation in the region of presumptive ventral epidermis in a non-pigmented Triturus cristatus early gastrula. The donor tissue induces a secondary invagination in the host embryo and exerts organizing activity to surrounding host tissues. A secondary embryo forms where the donor tissue contributes mainly to notochord and prechordal mesoderm structures and re-organizes the normally ventral surrounding host tissues, which are dorsalized into neural tube and mesoderm (adapted from Gilbert, Developmental Biology)

Fig. 2

Specification of tissues involved in patterning the anterior forebrain in the post-implantation mouse embryo and establishment of the anterio-posterior axis. AVE cells are induced to form by signals from the epiblast acting on VE at the distal tip of the embryo by 5.5 dpc. AVE cells migrate anteriorly at 5.5 dpc, reach the boundary between the epiblast and extra-embryonic ectoderm in approximately 5–6 h and then start to move laterally. At 6.5 dpc, the PS elongates and the anterior movements of the ADE/AME displace and intermingle with the AVE. The forebrain domain including future anterior and posterior forebrain is patterned within the anterior portion of the presumptive neural ectoderm that overlies AVE and ADE/AME tissues. By 7.5 dpc, the prospective anterior forebrain neural ectoderm overlies the ADE/AME and posterior neural tissue is underlied by the notochordal plate. VE visceral endoderm, AVE anterior visceral endoderm, ADE anterior definitive endoderm, AME anterior mesendoderm, np notochordal plate, PS primitive streak, AF anterior forebrain primordium, Ec neural ectoderm

Fig. 3

Subdivision of the neural plate in discreet gene expression domains. a At presomitic/early somite stages, in situ hybridization for Hesx1 (red) and Pax2 (purple), marking the anterior forebrain and posterior forebrain/midbrain precursors, respectively. b The anterior forebrain primordium express Hesx1 (red), and Pax3 (purple), delineates a posterior-lateral domain that gives rise to neural crest cells in an older embryo. Note that these domains do not overlap (adapted with permission from Disease Models and Mechanisms (Sajedi et al. (2008), Disease Models and Mechanisms 1 (4–5), 241–254)

Fig. 4

A host of signals act in concert to confer anterior forebrain identity. Signals such as WNTs, FGFs, and BMPs exert a posteriorizing action on the neural plate (blue arrows). Counteracting activation of the respective pathways in the anterior forebrain, secreted inhibitors such as Cerberus, Lefty1, Dkk1, Noggin, and Chordin (red arrows) are released by the underlying AVE, ADE, and prechordal plate. Within the prospective anterior forebrain, intrinsic factors such as HESX1, SIX3, and TCF3, aid in regulating the competence of neural tissue to not respond to posteriorizing signals, possibly by preventing the expression of target genes of these pathways, hence maintaining anterior forebrain identity. AF anterior forebrain, PF posterior forebrain, MB midbrain, HB hindbrain, SC spinal cord, AVE anterior visceral endoderm, ADE anterior definitive endoderm, pp prechordal plate