The Questions of Developmental Biology

The factors secreted from the ureteric bud include fibroblast growth factor 2 (FGF2) and
bone morphogenetic protein 7 (BMP7). FGF2 has three modes of action in that it inhibits
apoptosis, promotes the condensation of mesenchyme cells, and maintains the synthesis of WT1
(Perantoni et al. 1995). BMP7 has similar effects, and in the absence of BMP7, the mesenchyme
of the kidney undergoes apoptosis (see Figure 4.21; Dudley et al. 1995; Luo et al. 1995).
Step 4: LIF from the ureteric bud induces the mesenchyme cells to aggregate and to secrete wnt4
The ureteric bud also causes dramatic changes in the behavior of the metanephrogenic
mesenchyme cells, converting them into an epithelium. The newly induced mesenchyme
synthesizes two adhesive proteins, E-cadherin and syndecan (Figure 14.22; Vainio et al. 1989,
1992), which clump the mesenchyme together. These aggregated nodes of mesenchyme now
synthesize an epithelial basal lamina containing type IV collagen and laminin. At the same time,
the mesenchyme cells synthesize receptors for laminin, and this allows the aggregated cells to
become an epithelium (Ekblom et al. 1994; Müller et al. 1997). The cytoskeleton also changes
from one characteristic of mesenchyme cells to one typical of epithelia* (Ekblom et al. 1983;
Lehtonen et al. 1985).
The transition from mesenchymal to epithelial organization may be mediated by several
molecules. FGF2 is needed to induce the aggregation of the mesenchyme cells, but it is not
capable of turning these aggregates into epithelial cells (Karavanova et al. 1996). Leukemia
inhibitory factor (LIF) is able to convert these mesenchymal aggregates into kidney tubule
epithelium (but only if they have been exposed to FGF2) (Figure 14.23; Barasch et al. 1999). The
ureteric bud secretes FGFs and LIF, and the mesenchyme has receptors for these proteins.
Once induced, and after it has started to
condense, the mesenchyme begins to secrete
Wnt4, which acts in an autocrine fashion to
complete the transition from mesenchymal mass
to epithelium (Stark et al. 1994; Kispert et al.
1998). Wnt4 expression is found in the
condensing mesenchyme cells, in the S-shaped
tubes, and in the region where the newly
epithelialized cells fuse with the ureteric bud
tips. In mice lacking the Wnt4 gene, the mesenchyme becomes condensed but does not form
epithelia. Therefore, the ureteric bud induces the changes in the metanephrogenic mesenchyme by
secreting FGFs and LIF, but these changes are mediated by the effects of the mesenchyme's
secretion of Wnt4 on itself.