Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function

Abstract

Targeted gene disruption in the mouse shows that the Sonic hedgehog (Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial skeleton and the limbs. Early defects are observed in the establishment or maintenance of midline structures, such as the notochord and the floorplate, and later defects include absence of distal limb structures, cyclopia, absence of ventral cell types within the neural tube, and absence of the spinal column and most of the ribs. Defects in all tissues extend beyond the normal sites of Shh transcription, confirming the proposed role of Shh proteins as an extracellular signal required for the tissue-organizing properties of several vertebrate patterning centres.

Turning heads: Development of vertebrate branchiomotor neurons

“…In chick explant studies, sonic hedgehog (shh) -expressing tissue such as the notochord or recombinant Shh protein are sufficient to induce motor neurons in ventral neural tube explants derived from various axial levels, and this effect is blocked by antiShh antibodies Tanabe et al, 1995;Ericson et al, 1996). Furthermore, motor neurons are completely absent in Shh knockout mouse embryos (Chiang et al, 1996;Litingtung and Chiang, 2000a). Because zebrafish express multiple hedgehogs in the floor plate and notochord (Krauss et al, 1993;Ekker et al, 1995;Currie and Ingham, 1996), motor neurons are decreased but not lost completely in the zebrafish shh mutant (Chandrasekhar et al, 1998;Schauerte et al, 1998).…”

Expression and functional analysis of Tgif during mouse midline development

“…Sonic hedgehog (Shh) has been identified as a key signaling molecule from the prechordal plate to induce ventral forebrain specification, and targeted disruption of the Shh gene in the mouse leads to severe ventral midline defects, including cyclopia (Chiang et al, 1996). The TGF-␤ signaling pathway is essential for the formation and patterning of functional axial mesendoderm and definitive endoderm.…”

Loss of procollagen IIA from the anterior mesendoderm disrupts the development of mouse embryonic forebrain

“…AME expresses signaling ligands such as SHH (Shimamura and Rubenstein, 1997;Gunhaga et al, 2000) and BMP7 (Furuta et al, 1997), and modulators of signaling activity including CHRD, NOG, CER-BERUS, and DKK1 (Biben et al, 1998;Belo et al, 2000;Anderson et al, 2002;Kemp et al, 2005) which act synergistically to regulate the temporal-spatial activity of signaling pathways for forebrain induction and patterning (Dale et al, 1997(Dale et al, , 1999del Barco Barrantes et al, 2003). We have shown that deficiency of IIA in mice results in loss of expression of Shh in the prechordal plate and reduced Six3 and Pax2 expression in the forebrain, and phenocopies the malformation of the prosencephalon and mid-facial structures of the Shhnull mutant (Chiang et al, 1996). Although SHH activity is still maintained in the other segments of the AME, the morphogenesis of the forebrain is impaired in the IIA À/À mutant embryo.…”

“…Deletion of the anterior segment of the AME, containing the prechordal plate and part of the head process underneath the fore-and midbrain, also results in head truncation, but there is an up-regulation of Gsc and Shh expression in the remaining AME and expression of ventral forebrain markers (Six3 and Nkx2.1) in the rostral part of the truncated neural tube (Camus et al, 2000). Consistent with this finding, loss of SHH is associated with the loss of ventral telencephalic structures, accompanied by expansion of dorsal structures (Chiang et al, 1996); and provision of SHH to neural plate explants that lack AME could reconstitute expression of Nkx2.1, indicating the induction of ventral forebrain characteristics (Shimamura and Rubenstein, 1997). Genetic study of Ssdp1 function in the headshrinker mutant (Nishioka et al, 2005) and the interaction of Dkk1 and Gsc in the compound mutant (Lewis et al, 2007) shows that loss of these gene activities in the prechordal part of the AME has a significant impact on head formation.…”

“…Morphogenetic activity of prechordal tissue and anterior mesendoderm, mediated by SHH signaling is reputed to play a key role in the development of the embryonic forebrain (Chiang et al, 1996). In the headfold to foursomite stage IIA À/À embryo, Shh expression was reduced in the prechordal AME (n ¼ 5/8, Fig.…”