1599.5 Early Kidney Specification
All somatic tissues develop from the epiblast of the fertilized egg (E5.5 in mice). At
E6.5 the embryo develops a primitive streak (PS) in the posterior region, in an area
marked by the expression of transcription factor T (Brachyury) (Fig. 9.3a). The
epiblast cells which migrate through the PS differentiate to form the nascent endo-
derm and mesoderm (Tam and Loebel 2007 ). As the kidney derives from mesoder-
mal tissue, it is widely accepted that the kidney develops via the T-positive
population. The T-positive nascent mesoderm becomes further specified into three
subdomains along the dorsoventral axis: the paraxial mesoderm (PAM), intermedi-
ate mesoderm (IM), and a lateral plate mesoderm (LPM). These divisions first
become apparent around E8.5 and are present until E9.5 in mice (Fig. 9.3b). The
urogenital system—including all the kidney rudiments—is derived from IM. The
IM further specifies along the anteroposterior (A-P) axis between E8.5 and E9.5,
differentiating into the pro-, meso-, and metanephric anlagen in an anterior-to-
posterior direction. A more complete understanding of the mechanisms underlying
both dorsoventral patterning within the mesoderm and A-P patterning within the IM
is therefore essential.
9.5.1 Positioning Within the Primitive Streak Influences
Mesoderm Dorsoventral Patterning
Development of the nascent mesoderm occurs during the gastrulation stage
(E6.5–E7.5 in mice) and is dependent on Nodal/activin, BMP, and WNT signaling
(Tam and Loebel 2007 ). This combination of signaling pathways together with FGF
establishes the primitive streak (Fig. 9.3a). The classic model explains germ layer
specification based on the anterior-to-posterior gradient of Nodal/activin signal and
the opposite concentration gradient of BMP. The anteriorly located cells within the
primitive streak are exposed to a high concentration of Nodal/activin signal and
develop into endoderm, whereas the posterior cells differentiate into mesoderm
under the influence of BMP. Indeed, directed differentiation experiments employing
pluripotent stem cells mimic findings that the combined actions of activin and BMP
promote differentiation of the epiblast to mesoderm or endoderm fates (Gadue et al.
2006 ; Murry and Keller 2008 ).
Dye labeling-based lineage tracing experiment in chick embryos at a late gastru-
lation stage showed that the anterior cellular population within the primitive streak
gives rise to the PAM, the posterior population to LPM, and the mid-streak cells to
IM (Psychoyos and Stern 1996 ). Therefore, the signals that determine the A-P axis
within the late primitive streak could specify the fate of future IM to some extent
(James and Schultheiss 2003 ) (Fig. 9.3b).
9 Early Kidney Specification and Its Recapitulation by Pluripotent Stem Cells