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Fig. 7. Model of how Wnt and Notch pathways interact to regulate the size of the
otic placode. (A) The generation of the otic placode can be divided
into three stages. Pax2 in the pre-otic field is induced by FGFs
(arrows). A gradient of Wnts (light blue) determines the size of the otic
field: above a certain threshold, Wnts drive cells towards an otic fate (dark
blue), and, below the threshold, cranial epidermis is formed (Foxi2)
(Ohyama et al., 2006). Notch1
signaling is superimposed on the Wnt gradient (pink-blue) and acts to augment
the otic fate imposed by Wnts. NE, neuroectoderm; SE, surface ectoderm.
(B) The Wnt pathway is the primary signal (denoted by bold lettering)
that controls otic fate (blue region) by positively regulating (green arrows)
the expression of Dlx5, Sox9, Gbx2, Pax2, Pax8 and components of the
Notch1 pathway, such as Notch1 and Hes1 (Figs
1,
2). Jag1 expression is
initiated by Wnts (striped green arrow; see
Fig. 2). Notch1 acts to: (1)
augment Wnt and Notch1 activity within otic cells (pink arrow; plus sign); and
(2) co-operate with Wnt to negatively regulate Foxi2 (red) and
positively regulate Pax8 (dark green), and to maintain a thickened
otic placode. (C) A model summarizing the various otic placode
phenotypes observed in this study. A gradient of Wnt activity emanating from
the midline is established across the mediolateral axis of the pre-otic field.
Cells exposed to a certain threshold of Wnt signals express Jag1 and
differentiate as otic placode (blue). Below this threshold, cells
differentiate as epidermis (gray). Jag1-Notch1 signaling augments Wnt signals
in the medial region of the otic placode, whereas more lateral regions are not
exposed to Notch1 signals and Wnt signaling is not augmented. In the absence
of Notch1 (brown line), the gradient of Wnt signaling becomes weaker,
resulting in a smaller placode and more epidermis. When Notch1 is activated in
the pre-otic field (green line), the Wnt gradient is augmented further. Some
Wnt-dependent markers (Dlx5) are expressed only in the expanded Wnt
domain, whereas markers such as Pax8 are expressed throughout the
pre-otic field (marked as Pax8+ placode). When
β-catenin is activated in the entire pre-otic field (purple line), all
cells differentiate as otic placode
(Ohyama et al., 2006).
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