Metanephric kidney development begins with the formation of the metanephrogenic mesenchyme;
this event depends on the prior action in the intermediate mesoderm of transcription
factors such as Lim-1, Pax-2, Eya-1, and Foxc-1. Once it has formed, the mesenchyme
secretes GDNF; this induces the nearby wolffian duct to produce a ureteric bud which
invades the metanephrogenic mesenchyme and begins to arborize. Ureteric bud development
and branching depends on the transcription factor Emx-2, the GDNF-cRet and probably
the HGF/cMet, signalling systems, and the intracellular regulatory molecules formin
IV and timeless. Proteins of the BMP family modulate ureteric bud branching and keep
bud development in step with that of other tissue types. Proteins and glycosaminoglycans
of the matrix, and their receptors, and also required. The metanephrogenic mesenchyme
has a default fate of apoptosis and is dissuaded from suicide by factors secreted
from the bud such as TGF-α, TIMP-2, EGF, and FGF-2. Other factors such as LIF and
TGFβ2 cooperate with these to induce clumps of mesenchyme cells to differentiate into
nephrons, while BMP-7 appears to lead them instead to form stroma. As nephrons form,
they express critical transcription factors such as WT-1, Pax-2, and Hoxa11 and d11,
condense, and secrete Wnt-4. Wnt-4 acts in an autocrine loop to stimulate its own
synthesis and is required for cells to differentiate into epithelia; its action is
antagonized by sFRP-1, secreted by stroma, but this antagonism is itself inhibited
by sFRP-2 made by the developing nephron. This system probably acts both to limit
the spread of Wnt-4’s influence and also to commit responding cells to their epithelial
fate. As nephrons mature, regions of them differentiate to perform specific physiological
functions, a process that requires the proteins WT-1, Lmx-1b, Notch-2, Jagged-1, and
Hnf-1.