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Fig. 2. Molecular regulation of initial events in lung and tracheal
development. (A) The developing mouse foregut from embryonic day
(E) 8.0 to E9.0. (a) The Foxa and Gata transcription factors genes (yellow)
are involved in early events, such as foregut (Fg) tube closure and
establishing endodermal competence. (b,c) A model of foregut specification, in
which increasing thresholds of Fgfs (purple), emanating from the heart (Ht),
specify the ventral foregut endoderm into liver (Li) (blue line) or into lung
(Lu) and thyroid (Th) (red, Nkx2.1-expressing endoderm). [See text
and Serls et al. (Serls et al.,
2005) for details.] (B) Regulation of primary lung bud
formation, based on data from mouse and chick (see text for details). Foregut
mesoderm is shown in gray, endoderm in blue, and the endoderm of the
prospective trachea and lung in red. Lung budding (red) results from
mesodermal induction of Fgf10 and from activation of Fgfr2b signaling
in the endoderm (indicated by a yellow bracket). Retinoic acid (RA) and Tbx
genes (TBX4 in chicks) regulate Fgf10 expression.
Gli2 and Gli3 are both required for primary lung bud
formation, presumably via an unknown intermediate factor (X). Bmp4 is
expressed in the ventral mesoderm at the lung field, where its role is
unknown. (C) Trachea (Tr) formation from the ventral foregut and its
separation from the dorsal gut tube (Es, primitive esophagus). A cross-section
through the foregut shows dorsoventral (DV) differences in gene expression
that probably influence this process. For example, mice deficient in
Shh or Nkx2.1, which are normally present in the ventral
foregut endoderm, show tracheoesophageal fistula (incomplete separation of the
respiratory and digestive systems) (Minoo
et al., 1999; Litingtung et
al., 1998). This defect has been also associated with deficiencies
in Foxf1 (Lim et al.,
2002), Tbx4
(Sakiyama et al., 2003) and
RA (Dickman et al., 1997).
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