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Fig. 4. The midline phenotype in the Shh mutant differs from that in
the Bmpr1a;Bmpr1b mutant mouse. TUNEL analysis
(A,B) and RNA in situ hybridization (C-H) on E10.5
coronal sections. (A,B) TUNEL-positive cells are detected at the most
dorsomedial neuroepithelium in the Shh mutant (B, arrowhead), where
apoptosis occurs in control embryos (A, arrowhead). (C-H) The dorsal midline
markers Msx1 (C,D) and Bmp4 (E,F) are expressed in the
Shh mutant (arrowheads) and Foxg1 remains excluded from that
area (H, arrowheads). Scale bar: 200 µm. (I) Model illustrating
distinct mechanisms of HPE. In the wild type (left), BMPs acting downstream of
GLI3 (Grove et al., 1998 ;
Kuschel et al., 2003;
Theil et al., 1999) and ZIC2
are both required for the formation of the dorsal midline (ZIC2 is also
required ventrally). Note that Fgf8 may also regulate dorsal midline
development (Crossley et al.,
2001), although only reduction, not loss, of Fgf8
expression leads to dorsal HPE (Storm et
al., 2006). SHH acts indirectly to generate ventral cells by
antagonizing GLI3, which in turn relieves the repression of Fgf expression
(Aoto et al., 2002;
Gutin et al., 2006;
Rallu et al., 2002). In the
Bmpr double mutant (middle), the dorsal midline fails to form despite the
maintenance of Zic2 expression. However, ventromedial cell fates are
not affected, as is also the case in the MIH subclass of HPE. In the
Shh mutant and other mutants in which SHH signaling is disrupted
(right), dorsal midline features are initiated but ventromedial cells are
lost.
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