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Embryology of the Kidney
Rizaldy Paz Scott |^ Yoshiro Maezawa |^ Jordan Kreidberg |
Susan E. Quaggin
MAMMALIAN KIDNEY DEVELOPMENT
ANATOMIC OVERVIEW OF THE
MAMMALIAN KIDNEY
The kidney is a sophisticated, highly vascularized organ that
plays a central role in overall body homeostasis. In humans,
the kidneys filter as much as 180 liters of blood per day,
receiving as much as ~20% of the total cardiac output. Renal
filtration of blood removes metabolic waste products (e.g.,
urea, ammonia, and by-products of bile from the liver) as
urine while concomitantly adjusting the levels of water,
electrolytes, and pH of tissue fluids. Additionally, the kidneys
regulate blood pressure via the renin-angiotensin-aldosterone
system, secrete erythropoietin that stimulates erythrocyte
production, and contribute to the activation of vitamin D to
control calcium and phosphate balance.
The filtration function of the kidneys is accomplished by
basic units called nephrons (Fig. 1.1). Humans on average
have 1 million nephrons per adult kidney but the range of
total nephrons is highly variable across human populations.
4
Each mouse kidney may contain up to 12,000–16,000 nephrons
depending on the strain.
5
This wide range in nephron number
is influenced by genetic background, fetal nutrition and
environment, and maturity at birth.
6,
Nephron endowment
can be clinically important as markedly reduced nephron
numbers raises the susceptibility risk to hypertension and
chronic kidney disease.
1–3,8,
At the core of the nephron is the
renal corpuscle or glomerulus (see Fig. 1.1). The glomerulus
consists of a porous and highly convoluted capillary bed
composed of highly fenestrated glomerular endothelial cells.
These glomerular capillaries are circumscribed by morpho-
logically elaborate and interdigitating cells called podocytes.
These capillaries are further structurally supported by pericytes
CHAPTER OUTLINE
MAMMALIAN KIDNEY DEVELOPMENT, 2
MODEL SYSTEMS TO STUDY KIDNEY
DEVELOPMENT, 8
GENETIC ANALYSIS OF MAMMALIAN
KIDNEY DEVELOPMENT, 15
MOLECULAR GENETICS OF
NEPHROGENESIS, 22
KEY POINTS
- The development of the kidney relies on reciprocal signaling and inductive interactions
between neighboring cells.
- Epithelial cells that comprise the tubular structures of the kidney are derived from two distinct
cell lineages: the ureteric epithelia lineage that branches and gives rise to collecting ducts
and the nephrogenic mesenchyme lineage that undergoes mesenchyme to epithelial
transition to form connecting tubules, distal tubules, the loop of Henle, proximal tubules,
parietal epithelial cells, and podocytes.
- Nephrogenesis and nephron endowment requires an epigenetically regulated balance
between nephron progenitor self-renewal and epithelial differentiation.
- The timing of incorporation of nephron progenitor cells into nascent nephrons predicts their
positional identity within the highly patterned mature nephron.
- Stromal cells and their derivatives coregulate ureteric branching morphogenesis,
nephrogenesis, and vascular development.
- Endothelial cells track the development of the ureteric epithelia and establish the renal
vasculature through a combination of vasculogenic and angiogenic processes.
- Collecting duct epithelia have an inherent plasticity enabling them to switch between
principal and intercalated cell identities.
CHAPTER 1 — EmbRyology of THE KidNEy 3
called mesangial cells. Blood filtration occurs through this
capillary tuft, generating primary urine that collects within the
Bowman capsule, an enclosure formed by parietal epithelial
cells. From the Bowman capsule, urine drains through a
series of tubules starting with the proximal tubules, the loop
of Henle, the distal tubules, and the collecting ducts. These
tubules are responsible for dynamic resorption and secretion
processes that help recycle filtered small molecules; they also
adjust water, electrolyte, and acid–base balance by fine-tuning
the composition of the final urine output before it exits the
ureter and is excreted via the bladder. Supporting the main
functions of the nephrons are interstitial fibroblasts and a
heterogenous network of extraglomerular vasculature.
DEVELOPMENT OF THE UROGENITAL SYSTEM
The vertebrate kidney derives from the intermediate meso-
derm of the urogenital ridge, a structure found along the
posterior wall of the abdomen in the developing fetus.
10,
Mammalian kidneys develop in three successive stages,
generating three distinct excretory structures known as the
pronephros, the mesonephros, and the metanephros (Fig.
1.2). The pronephros and mesonephros are vestigial structures
in mammals and degenerate before birth; the metanephros
is the definitive mammalian kidney. The early stages of kidney
development are required for the development of the adrenal
glands and gonads that also form within the urogenital ridge.
Furthermore, many of the signaling pathways and genes that
play important roles in the metanephric kidney appear to
play parallel roles during the development of the pronephros
Fig. 1.1 Anatomic organization of the kidney. (A) Spatial distribution of nephron within the metanephric kidney. Glomeruli, the filtration
compartments of the nephrons, are found in the cortex. (B) Segmental structure of nephrons. The vascularized glomerulus is found at the
proximal end and is connected through a series of renal tubules where urinary filtrate composition is refined through resorption and secretion.
(C) Cellular organization of the glomeruli. AA, Afferent arteriole; BS, Bowman space; CD, Collecting duct; DT, distal tubule; EA, efferent arteriole;
GEC, glomerular endothelial cell; LOH, loop of Henle; MC, mesangial cell; PEC, parietal epithelial cell; Pod, podocyte; PT, proximal tubule.
Reproduced with permission from Scott RP, Quaggin SE. The cell biology of renal filtation. J Cell Biol. 2015;209:100–210.
Fig. 1.2 Three stages of mammalian kidney development. The
pronephros and mesonephros develop in a rostral-to-caudal direction
and the tubules are aligned adjacent to the wolffian or nephric duct
(WD). The metanephros develops from an outgrowth of the distal end
of the wolffian duct known as the ureteric bud epithelium (UB) and a
cluster of cells known as the metanephric mesenchyme (MM). The
pronephros and mesonephros are vestigial structures in mice and
humans and are regressed by the time the metanephros is well
developed.
CHAPTER 1 — EmbRyology of THE KidNEy 5
UB (Fig. 1.5). Whereas each nephron is an individual unit
separately induced and originating from a distinct pretubular
aggregate, the collecting ducts are the product of branching
morphogenesis from the UB. Considerable remodeling is
involved in forming collecting ducts from branches of the
UB.
15
The branching is highly patterned, with the first several
rounds of branching being somewhat symmetric, followed
by additional rounds of asymmetric branching, in which a
main trunk of the collecting duct continues to extend toward
the nephrogenic zone, while smaller buds branch as they
induce new nephrons within the nephrogenic zone. Originally,
the UB derivatives are branching within a surrounding
mesenchyme. Ultimately, they form a funnel-shaped structure
in which cone-shaped groupings of ducts or papillae sit within
a funnel or calyx that drains into the ureter. The mouse
kidney has a single papilla and calyx, whereas a human kidney
has 8 to 10 papillae, each of which drains into a minor calyx,
with several minor calyces draining into a smaller number
of major calyces.
DEVELOPMENT OF THE NEPHRON
The renal vesicle undergoes patterned segmentation and
proceeds through a series of morphologic changes that
include gradual recruitment of mesenchymal progenitors to
form the glomerulus and components of the nephrogenic
tubules from the proximal convoluted tubule, the loop of
Henle, and the distal tubule. The renal vesicles undergo
differentiation, passing through morphologically distinct
stages starting from the comma-shaped and proceeding to
the S-shaped body, capillary loop, and mature stage, each
step involving precise proximal-to-distal patterning and
structural transformations (see Fig. 1.4). Remarkably, this
process is repeated 600,000 to 1 million times in each develop-
ing human kidney as new nephrons are sequentially born
at the tips of the UB throughout fetal life.
The glomerulus develops from the most proximal end of
the renal vesicle that is furthest from the UB tip.
16,
Distinct
cell types of the glomerulus can first be identified in the
S-shaped stage, where presumptive podocytes appear as a
columnar-shaped epithelial cell layer. A vascular cleft develops
and separates the presumptive podocyte layer from more
distal cells that will form the proximal tubule. Parietal epi-
thelial cells differentiate and flatten to form the Bowman
capsule, a structure that surrounds the urinary space and is
continuous with the proximal tubular epithelium. Concur-
rently, endothelial cells migrate into the vascular cleft.
Together with podocytes, the endothelial cells produce the
glomerular basement membrane, a major component of the
mature filtration barrier. Initially the podocytes are connected
by intercellular tightjunctions at their apical surface.
18
As
glomerulogenesis proceeds, the podocytes flatten and spread
out to cover the increased surface area of the growing glo-
merular capillary bed. They develop microtubular-based
primary processes and actin-based secondary foot processes.
19–
Foot processes of neighboring podocytes interdigitate and
elongate. As podocytes mature, intercellular epithelial tight
junctions linking become restricted to the basal aspect of
the podocyte, relocate from the cell body to the foot processes,
and are eventually replaced by a modified adherens junction-
like structure known as the slit diaphragm.
18,
The slit dia-
phragms are signaling hubs serving as the final layer of the
glomerular filtration barrier.
23
Mesangial cell ingrowth follows
Table 1.1 Timelines of Human and Mouse
Kidney Development
Stage/Event Human
a Mouse
b
Pronephros
- Emergence
- Disappearance by
22nd day
25th day
E
E
Mesonephros
- Emergence
- Disappearance by
24th day
16th week
E
E
Metanephros
- Ureteric bud induction
- Nephrogenesis
- Glomerulogenesis
- Cessation of nephrogenesis
28th–32nd day
44th day
8th–9th week
36th week
E10.
E
E
P
Gestation (Total Length) 40 weeks 19–21 days
a Human timelines refer to gestational periods. b Mouse timelines are indicated as either embryonic days post
coitum (E) or postnatal (P).
A
B C
D
Fig. 1.4 The collecting duct system. The branching ureteric epithelia
gives rise to the collecting duct system. (A) E12.5 mouse embryonic
kidney explant grown for 2 days and (B) neonatal mouse kidney section
stained for the ureteric epithelium and collecting ducts (pan-cytokeratin,
red ) and proximal tubules (Lotus lectin, green ). (C) Scanning electron
micrograph of a hemisected adult mouse kidney showing the funnel-
shaped renal papilla. (D) Scanning electron micrograph of a collecting
duct showing smooth principal cells and reticulated intercalated cells.
6 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
The distal tubule is contiguous with the collecting duct, a
derivative of the UB. Imaging and fate mapping studies reveal
that this interconnection results from the invasion of the
UB by cells from the distal segments of nascent nephrons
(around the S-shaped body stage).
25
Although all segments of the nephron are present at birth
and filtration occurs prior to birth, maturation of the tubule
continues in the postnatal period. Increased expression levels
of transporters, switches in transporter isoforms, alterations
in paracellular transport mechanisms, and permeability and
biophysical properties of tubular membranes have all been
observed to occur postnatally.
26
These observations emphasize
the importance of considering the developmental stage of
the nephron in interpretation of renal transport and may
explain the age of onset of symptoms in inherited transport
disorders.
THE NEPHROGENIC ZONE
After the first few rounds of branching of the UB, and the
concomitant induction of nephrons from the MM, the kidney
subdivides into two major compartments: an outer region
called the cortex and an inner region called the medulla.
The glomeruli and proximal and distal tubules localize within
the migration of endothelial cells and is required for develop-
ment and patterning of the capillary loops that are found
in normal glomeruli. The endothelial cells also flatten
considerably and capillary lumens are formed due to apoptosis
of a subset of endothelial cells.
24
At the capillary loop stage,
glomerular endothelial cells develop fenestrae, which are
semipermeable transcellular pores common in capillary beds
exposed to high hemodynamic flux.
In the mature stage glomerulus, the podocytes, fenestrated
endothelial cells, and intervening glomerular basement
membrane comprise the filtration barrier that separates the
urinary from the blood space. Together, these components
provide a size- and charge-selective barrier that permits free
passage of small solutes and water but prevents the loss of
larger molecules such as proteins. The mesangial cells are
found between the capillary loops where they are required
to provide ongoing structural support to the capillaries and
possess smooth-muscle cell-like characteristics that have the
capacity to contract, which may account for some of the
dynamic properties of the glomerulus. The tubular portion
of the nephron becomes segmented in a proximal–distal
order, into the proximal convoluted tubule, the descending
and ascending loops of Henle, and distal convoluted tubule.
A
B
C
D
E
F
Ureter
Pelvis Papilla
Medulla
Cortex
NZ
PA
UB
CSB
EC
SSB
UB
CT
DT
PT
BC
EC
LH
CD
PT
CT
DT
CM
UB
GC
BC
RV
Fig. 1.5 Overview of nephrogenesis. (A) Gross kidney histoarchitecture. (B–E) As described in the text, reciprocal interaction between the
ureteric bud and metanephric mesenchyme results in a series of well-defined morphologic stages leading to formation of the nephron, including
the branching of the UB epithelium and the epithelialization of the metanephric mesenchyme into a highly patterned nephron. (F) Distinctive
segmentation of the S-shaped body defines the patterning of the nephron. BC, Bowman capsule; CD, collecting duct; CM, cap mesenchyme;
CSB, comma-shaped body; CT, connecting tubule; DT, distal tubule; EC, endothelial cells; LH, loop of Henle; NZ, nephrogenic zone; PA,
pretubular aggregate; PT, proximal tubule; SSB, S-shaped body; UB, ureteric bud.
8 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
maturation is largely restricted in embryonic kidney explants,
in vitro cultured kidneys display remarkable recapitulation
of ureteric branching and epithelialization and segmental
patterning of the MM (Fig. 1.10). Historically, kidney explant
cultures provided crucial proof for the principle of reciprocal
tissue induction in organogenesis. It was used to demonstrate
that the UB and the MM exchange inductive cues, driving
branching morphogenesis of the UB and epithelialization
of the MM.
10,
As originally shown by Grobstein, Saxen, and colleagues,
the two major components of the metanephric kidney, the
MM and the UB, could be separated from each other, and
the isolated mesenchyme could be induced to form nephron-
like tubules by a selected set of other embryonic tissues, the
best example of which is the embryonic neural tube.
10,
When
the neural tube is used to induce the separated mesenchyme,
there is terminal differentiation of the mesenchyme into
tubules, but not significant tissue expansion. In contrast,
intact metanephric rudiments can grow more extensively,
glomerular capillary loops. The efferent arterioles carry blood
away from the glomerulus to a system of fenestrated peritu-
bular capillaries that are in close contact with the adjacent
tubules and receive filtered water and solutes reabsorbed
from the filtrate.
36
These capillaries have few pericytes. In
comparison, the vasa rectae, which surround the medullary
tubules and are involved in urinary concentration, are also
fenestrated but have more pericytes. They arise from the
efferent arterioles of deep glomeruli.
37
The peritubular
capillary system surrounding the proximal tubules is well
developed in the late fetal period, whereas the vasa rectae
mature 1 to 3 weeks postnatally.
MODEL SYSTEMS TO STUDY KIDNEY
DEVELOPMENT
THE KIDNEY ORGAN CULTURE SYSTEM
From the late 1950s, the method of growing mouse embryonic
kidneys as floating cultures on top of filters (Fig. 1.9), a
technique pioneered by Clifford Grobstein and improved
by Lauri Saxen, accelerated the advancement of the kidney
developmental biology field. This classic method, which
remains widely in use to this day, has the advantages that
the kidney explants are cultivated within an easily manipu-
lated, controlled environment, and there is a possibility of
visualizing the pattern of kidney growth by real-time fluo-
rescence microscopy. Although vascularization and functional
Fig. 1.7 The renal vasculature. (A) Visualization of the renal vascular
network in a reporter mouse strain expressing prokaryotic β-
galactosidase through the promoter of the vascular-specific phos-
phatase gene Ptprb. (B) Higher magnification of the renal cortex in
(A) showing endothelial cell distribution in glomeruli ( yellow arrowheads ),
arterioles, peritubular capillaries, and arcuate arteries. (C) Corrosion
resin cast of the renal vasculature revealing the highly convoluted
assembly of the glomerular capillaries (g). (D) Scanning electron
micrograph of a glomerulus with an exposed endothelial lumen ( dashed
outline ) revealing fenestrations. EC, Endothelial cell; Pod, podocytes.
Corrosion cast electron micrograph courtesy Fred Hossler, Department
of Anatomy and Cell Biology, East Tennessee State University.
A
BB
C
Fig. 1.8 Angiogenesis and vasculogenesis in renal vascular
development. Schematic overview of early development of the renal
vasculature. (A) Angiogenesis generates major blood vessels through
sprouting and branching of pioneer vessels ( red ) that follow the
branching ureteric bud ( brown ). (B) Scattered endothelial progenitor
cells ( yellow ) are distinctly present as early as E11.5 at the periphery
of the developing metanephric kidney ( blue ). These sporadic endothelial
cells coalesce and organize into a primitive capillary plexus ( yellow )
by E12.5. (C) Major vessels formed via angiogenesis and capillaries
that arise by vasculogenesis become interconnected to establish the
elaborate renal vascular network. Adapted from Stolz DB, Sims-Lucas
S. Unwrapping the origins and roles of the renal endothelium. Pediatr
Nephrol. 2015;30:865–872.
CHAPTER 1 — EmbRyology of THE KidNEy 9
A B
C D
Fig. 1.9 Metanephric organ explants. (A, B) Top and (C) lateral view of a kidney organ culture. Embryonic kidney explants are grown at the
air–growth medium interface on top of a floating porous polycarbonate filter ( dashed lines in A) supported on a metal mesh. (D) Kidneys grown
after 4 days of culture. Reproduced with permission from Cold Spring Harbor Protocols.
741
A B
D
E
F
G
H
C
Fig. 1.10 Recapitulation of branching and nephrogenesis in renal explant cultures. (A) Ureteric tree stained for cytokeratin 8 (Cyk8). (B)
Condensed metanephric mesenchyme stained for WT1. (C) Epithelial derivatives of the metanephric mesenchyme stained for E-cadherin ( Cdh1 ).
(D) Proximal tubules stained with Lotus tetraglobulus lectin (LTL). (E) Merged image of A–D. (F) WT1 -expressing cells represent the nephron
progenitor cells that surround the UB. (G) Cdh1 -expression marks the mesenchyme-to-epithelial transformation of nephron progenitor cells.
(H) Early patterning of nascent nephrons along a proximodistal axis. Reproduced with permission from Cold Spring Harbor Protocols.
741
displaying both sustained UB branching and early induction
of nephrons even when cultured for a week. The isolated
mesenchyme experiment has proven useful in the analysis
of renal agenesis phenotypes, where there is no outgrowth
of the UB. In these cases, the mesenchyme can be placed
in contact with the neural tube to determine whether it has
the intrinsic ability to differentiate. Most often, when renal
agenesis is due to the mutation of a transcription factor,
tubular induction is not rescued by the neural tube, as could
be predicted for transcription factors, which would be
expected to act in a cell-autonomous fashion.
39
In the converse
situation, in which renal agenesis is caused by loss of a gene
function in the UB (e.g., Emx2 ), it is usually possible for the
embryonic neural tube to induce tubule formation in isolated
mesenchymes.
40
Therefore the organ culture induction assay
can be used to test hypotheses concerning whether a particular
CHAPTER 1 — EmbRyology of THE KidNEy 10.e
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Renal Agenesis
Celsr1 Renal agenesis, hydroureter,
hydronephrosis
Spina bifida, unilateral renal
agenesis, hydronephrosis
Ctnnb1 (β-catenin) Renal agenesis or severe renal
hypoplasia, premature differentiation
of UB epithelia (UB-selective)
Mental retardation, multiple
cancers, eye defects
Emx2 Renal agenesis Schizencephaly (cerebral cleft
abnormalities)
Emx2, Pax2 Duplicated kidneys and ureter, ureteral
obstruction
CAKUT, VUR 531
Esrp1 Renal agenesis, renal hypoplasia 532
Etv4, Etv5 Renal agenesis or severe renal
hypodysplasia
Eya1 Renal agenesis Branchiootorenal syndrome
(brachial fistulae, deafness)
Fgf9, Fgf20 Renal agenesis 305
Fgf10, Gdnf, Gfra1 Renal agenesis 222
Fgfr1, Fgfr2 Renal agenesis
(MM-selective)
Fras1, Frem1, Frem2 UB failure, defect of GDNF expression Fraser syndrome (cryptophthalmos,
syndactyly, CAKUT);
Manitoba-oculo-tricho-anal (MOTA)
syndrome
Gata3 Renal agenesis, gonad dysgenesis
(null mutation)
Hypoparathyroidism, sensorineural
deafness, and renal dysplasia
(HDRS) syndrome; autoimmune
disease
Gdf11 UB failure, skeletal defects 145, 533
Gdnf, Gfra1, Ret Renal agenesis or rudimentary
kidneys, aganglionic megacolon
Hirschsprung disease,
Multiple endocrine neoplasm
type IIA/B (MEN2A/MEN2B),
and familial medullary thyroid
carcinoma (FMTC)
Gen1 Renal agenesis, duplex kidneys,
hydronephrosis, ureteral obstruction
Gli3 Renal agenesis, severe renal agenesis,
absence of renal medulla and
papilla
Pallister-Hall (PH) syndrome
(polydactyly, imperforate anus,
abnormal kidneys, defects in the
gastrointestinal tract, larynx, and
epiglottis)
Greb1l Renal agenesis CAKUT 539–
Grem1 Renal agenesis; apoptosis of the MM 146
Grhl2 Occasional unilateral renal agenesis,
CD barrier dysfunction, diabetes
insipidus
Autosomal dominant deafness,
ectodermal dysplasia
Grip1 Renal agenesis Fraser syndrome (cryptophthalmos,
syndactyly, CAKUT)
Hnf1b Renal agenesis, renal hypoplasia,
hydroureter, duplex kidneys
CAKUT, diabetes mellitus, renal
cysts, renal carcinoma
Hoxa11, Hoxd11 Distal limbs, vas deferens Radioulnar synostosis
with amegakaryocytic
thrombocytopenia
Hs2st1 Lack of UB branching and
mesenchymal condensation
Isl1 Renal agenesis, renal hypoplasia,
hydroureter (MM-selective)
Itga8 (α8 Integrin) Renal agenesis, renal hypodysplasia Fraser syndrome (cryptophthalmos,
syndactyly, CAKUT)
Continued on following page
10.e2 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Itgb1 (β1 Integrin) Renal agenesis, disrupted UB
branching, hypoplastic collecting
duct system (collecting duct–
selective); podocyte dedifferentiation
(podocyte-selective)
Fraser syndrome (cryptophthalmos,
syndactyly, CAKUT)
Kif26b Renal agenesis, failed UB attraction to
the MM
Lamc1 UB failure, delayed nephrogenesis,
water transport defects
Lhx1 (Lim1) Renal agenesis (null mutant); renal
hypoplasia, UB branching defect,
hydronephrosis, distal ureter
obstruction (UB-selective); arrested
nephrogenesis, nephron patterning
defects (MM-selective)
Mayer-Rokitansky-Küster-Hauser
(MRKH) syndrome (müllerian
duct agenesis)
Lrp4 Delayed UB induction, failed MM
induction, syndactyly, oligodactyly
Cenani-Lenz syndrome 552–
Mark2 (Par1b), Mark
(Par1a)
Renal hypoplasia, proximal tubule
dilation, immature glomeruli
Npnt Delayed UB association with the MM 168
Osr1 Lack of MM, adrenal gland, gonads,
defects in formation of pericardium
and atrial septum
Pax2 Renal hypoplasia, VUR CAKUT, VUR, optic nerve
colobomas
Pax2, Pax8 Defect in intermediate mesoderm
transition, failure of pronephric duct
formation
CAKUT, VUR, optic nerve
colobomas
Pbx1 Unilateral renal agenesis, expansion of
nephrogenic precursors
CAKUT, hearing loss, abnormal
ears
Ptf1a Failure of UB induction, anal
atresia, persistent cloaca, skeletal
malformation
Pancreatic and cerebellar
agenesis; diabetes mellitus
Rara, Rarb Renal hypoplasia, dysplasia,
hydronephrosis, skeletal and
multiple visceral abnormalities
Sall1 Renal agenesis, severe renal
hypodysplasia
Townes-Brock syndrome (anal,
renal, limb, ear anomalies)
Shh Bilateral or unilateral renal agenesis,
unilateral ectopic dysplastic
kidney, defective ureteral stromal
differentiation
Vertebral defects, anal
atresia, cardiac defects,
tracheoesophageal fistula,
renal anomalies, and limb
abnormalities (VACTERL)
syndrome
Six1 Lack of UB branching and
mesenchymal condensation
Branchiootorenal syndrome 136, 150
Sox8, Sox9 Renal genesis, renal hypoplasia Campomelic dysplasia (limb and
skeletal defects, abnormal
gonad development)
Tln1, Tln2 Renal agenesis 566
Wnt5a Renal agenesis, renal dysplasia,
duplex kidneys, hydronephrosis
CAKUT 567–
Wt1 Renal and gonadal agenesis, severe
lung, heart, spleen, adrenal, and
mesothelial abnormalities
Wilms tumor, aniridia, genitourinary
abnormalities, and retardation
(WAGR) syndrome; Denys–Drash
syndrome
Hypoplasia/Dysplasia/Low Nephron Mass
Adamts1 Hypoplasia of the renal medulla,
hydronephrosis
Adamts1, Adamts4 Hypoplasia of the renal medulla,
hydronephrosis
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
10.e4 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Fgf10 Renal hypoplasia, multiorgan
developmental defects, including
the lungs, limb, thyroid, pituitary
and salivary glands
Fgfr1, Fgfr2 Renal agenesis (MM-selective) 304
Fgfr2 Renal hypoplasia, hydronephrosis
(UB-selective)
Foxc2 Renal hypoplasia Lymphedema-distichiasis
syndrome
Foxd1 Accumulation of undifferentiated CM,
attenuated UB branching, stromal
patterning defects
Frs2 Mild renal hypoplasia (UB-selective) 580
Fzd4, Fzd8 Impaired UB branching, renal
hypoplasia
Hdac1, Hdac2 Renal hypoplasia, renal dysplasia,
arrest of nephrogenesis at the renal
vesicle stage
Lats1, Lats2 Renal hypoplasia, impaired
UB-branching and UB tip
specification, impaired
nephrogenesis and renal interstitial
differentiation
Lgr4 Severe renal hypoplasia and
oligonephronia; renal cysts
Aniridia-genitourinary anomalies;
mental retardation
Lmx1b Renal dysplasia, skeletal abnormalities Nail–patella syndrome 435, 442
Map2k1 (Mek2), Map2k
(Mek1)
Renal hypodysplasia, megaureter Cardiofaciocutaneous syndrome 208
Mdm2 Renal hypoplasia and dysplasia,
severely impaired UB branching
and nephrogenesis (UB-selective);
depletion of nephrogenic precursors
(MM-selective)
Mf2 Renal hypoplasia, oligonephronia 589
Mitf Oligonephronia Microphthalmia, Waardenburg
syndrome type 2A
Nf2 Renal hypoplasia, renal dysplasia 584
Notch1, Notch2 Loss of nephron derivatives, nephron
segmentation defects
Alagille syndrome (cholestatic liver
disease, cardiac disease, kidney
dysplasia, renal cysts, renal
tubular acidosis)
Pbx1 Reduced UB branching, expansion
of nephrogenic precursors,
delayed mesenchyme-to-epithelial
transformation, dysgenesis of
adrenal gland and gonads
Plxnb2 Renal hypoplasia and ureter
duplication
Pou3f3 (Brn1) Impaired development of distal
tubules, loop of Henle, and macula
densa; distal nephron–patterning
defect
Prr Renal hypoplasia, renal dysplasia,
oligonephronia
Psen1, Psen2 Severe renal hypoplasia, severe
defects in nephrogenesis
Ptgs2 Oligonephronia 595
Rbpj Severe renal hypoplasia,
oligonephronia, loss of proximal
nephron segments, tubular cysts
(MM-selective)
Sall1 Severe renal hypoplasia, cystic
dysplasia of nephrogenic derivatives
(tubules and glomeruli)
Townes-Brocks branchiootorenal–
like syndrome
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
CHAPTER 1 — EmbRyology of THE KidNEy 10.e
Continued on following page
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Shp2 Severe impairment of UB branching,
renal hypoplasia
Six1 Hydronephrosis, hydroureter,
abnormal development of ureteral
smooth muscle
Six2 Renal hypoplasia and premature
depletion of nephrogenic precursors
(homozygous loss); increased
UB branching and augmentation
of nephron endowment
(haploinsufficiency)
Tbx18 Hydronephrosis, hydroureter,
abnormal development of ureteral
smooth muscle
Tfap2b MM failure, craniofacial and skeletal
defects
Trp53 (p53) Oligonephronia, precocious depletion
of nephrogenic precursors
Multiple cancers 599
Trps1 Impaired UB branching, renal
hypoplasia
Trichorhinophalangeal syndrome
(skeletal defects)
Vangl2 Impaired UB branching and renal
hypoplasia
Neural tube defects 332
Wnt4 Failure of MM induction 289
Wnt7b Complete absence of medulla and
renal papilla (UB-selective)
Wnt9b Vestigial kidney, failure of MM
induction; cystic kidney
(CD-selective)
Wnt11 Impaired ureteric branching, renal
hypoplasia
Yap Renal hypoplasia renal dysplasia,
hydronephrosis, severe disruption
of UB branching (UB-selective),
oligonephronia, defects in
mesenchyme to epithelial transition
(CM-selective)
Coloboma, hearing impairment,
cleft palate, cognitive deficit,
hematuria
Mislocalized or Ectopic UB/Increased UB Branching
Bmp4 Duplex ureter, hydroureter, renal
hypodysplasia
Microphthalmia, orofacial cleft 242
Cer1 Increased ureteric branching, altered
spatial organization of ureteric
branches
Cfl1 Renal hypodysplasia, ureter
duplication
Foxc1 Duplex kidneys, ectopic ureters,
hydronephrosis, hydroureter
Gata3 Ectopic ureteric budding, duplex
kidneys, hydroureter (UB-selective)
Hypoparathyroidism, sensorineural
deafness, and renal dysplasia
(HDRS) syndrome; autoimmune
disease (rheumatoid arthritis)
Hnf1b, Pax2 Renal hypoplasia, duplex kidneys,
ectopic ureters, megaureter,
hydronephrosis
CAKUT 602
Hspb11 (Ift25) Duplex kidneys 603
Ift27 Duplex kidneys 603
Lzts2 Duplex kidneys/ureters,
hydronephrosis, hydroureter
Plxnb1 Increased ureteric branching 605
Plxnb2 Renal hypoplasia and ureter
duplication
Robo2 Increased UB branching CAKUT, VUR 238, 239
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
CHAPTER 1 — EmbRyology of THE KidNEy 10.e
Continued on following page
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Later Phenotypes (Tubular, Vascular, and Glomerular Defects)
Ace Atrophy of renal papillae, vascular
thickening and hypertrophy,
perivascular inflammation
Chronic systemic hypotension 258, 259
Actn4 Glomerular developmental defects,
FSGS
SRNS 451, 452
Adam10 Loss of principal cells of the CD,
hydronephrosis, polyuria
Alzheimer disease; reticulate
acropigmentation of Kitamura
Agt Atrophy of renal papillae, vascular
thickening and hypertrophy,
perivascular inflammation
Chronic systemic hypotension 256, 427
Agtr1a (AT1A) Hypertrophy of juxtaglomerular
apparatus and expansion of renin
cell progenitors, mesangial cell
hypertrophy
Chronic systemic hypotension 633
Agtr1a/Agtr1b (AT1A/
AT1B)
Atrophy of renal papillae, vascular
thickening and hypertrophy,
perivascular inflammation
Chronic systemic hypotension 261
Ampd Podocyte foot process effacement,
proteinuria
Minimal change nephropathy 634
Angpt1 Simplification and dilation of
glomerular capillaries; detachment
of glomerular endothelium from the
GBM; loss of mesangial cells; loss
of ascending vasa recta (compound
deletion with Angpt2 )
Angpt2 Cortical peritubular capillary
abnormalities (null allele); apoptosis
of glomerular capillaries, proteinuria
(transgenic overexpression); loss of
ascending vasa recta (compound
deletion with Angpt1 )
Arhgdia (RhoGDIα) Podocyte effacement and proteinuria SRNS, FSGS 77, 80, 635
Bmp7 Hypoplastic kidney, impaired
maturation of nephron, reduced
proximal tubules (podocyte-
selective)
Cd151 Podocyte foot process effacement,
disorganized GBM, tubular cystic
dilation
Nephropathy (FSGS) associated
with pretibial epidermolysis
bullosa and deafness
Cd2ap Podocyte effacement, proteinuria FSGS 484
Cdc42 Congenital nephrosis; impaired
formation of podocyte foot
processes (podocyte-selective)
Cmas Congenital nephrosis; impaired
formation of podocyte foot
processes, defective sialylation
Col4a1, Col4a3,
Col4a4, Col4a
Disorganized GBM, proteinuria Alport syndrome 639–
Coq6 Nephrotic syndrome and deafness SRNS, FSGS, sensorineural
deafness
Crb2 Podocyte effacement and proteinuria SRNS, FSGS 644
Crk1, Crk2, CrkL Albuminuria, altered podocyte
cytoarchitecture (podocyte-
selective)
Cxcl12 (SDF1), Cxcr4,
Cxcr
Petechial hemorrhage in the kidneys,
glomerular aneurysm, fewer
glomerular fenestrations, reduced
mesangial cells, podocyte foot
process effacement, mild renal
hypoplasia
WHIM (warts,
hypogammaglobulinemia,
infections, and myelokathexis)
syndrome
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
10.e8 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Dicer1 Podocyte damage, albuminuria,
end-stage renal failure (podocyte-
selective); reduced renin production,
renal vascular abnormalities, striped
fibrosis (renin cell–selective)
Pleuropulmonary blastoma 430, 492–
Dnm1, Dnm2 (Dynamin
1/2)
Podocyte foot process effacement
and proteinuria (podocyte-selective)
Dot1l Increased intercalated at the expense
of principal CD cells; polyuria
Efnb1 (Ephrin B1) Podocyte foot process effacement
and proteinuria (podocyte-selective)
Efnb2 (Ephrin B2) Dilation of glomerular capillaries 396
Egln1 (Phd2), Egln
(Phd3)
Renal hypoplasia, oligonephronia,
abnormal postnatal nephron
formation, abnormally elevated
erythropoietin production,
dilation of renal blood vessels,
glomerulosclerosis (stroma-specific)
Familial erythrocytosis; abnormally
high EPO levels; high altitude
adaptation hemoglobin (HALAH)
Elf5 Paucity in principal CD cells 274
Fat1 Foot process fusion, failure of foot
process formation, proteinuria
SRNS, FSGS, hematuria with
neurologic defects; glioblastoma,
colorectal cancer, head and
neck cancer
Fermt2 (Kindlin-2) Rac1 hyperactivation, podocyte
effacement and proteinuria
Flt1 (Vegfr1) Nephrotic syndrome 491
Foxc1 and Foxc2 Impaired podocyte differentiation,
dilated glomerular capillary
loop, poor mesangial migration;
proteinuria and glomerulosclerosis
Anterior segment dysgenesis/
Axenfeld-Rieger syndrome
(iris hypoplasia and defective
cornea); lymphedema-
distichiasis syndrome (lower limb
swelling and extra eyelashes)
Foxi1 Tubular acidosis; absence of CD
intercalated cells
Tubular acidosis and deafness 268, 269
Fyn Podocyte foot process effacement,
abnormal slit diaphragms,
proteinuria
Gata3 Impaired maintenance of mesangial
cells, dilation of glomerular
capillaries, glomerulosclerosis
and mesangial matrix expansion,
proteinuria
Gnas (Gαs) FSGS, mesangial expansion,
proteinuria, urinary concentration
defect (renin cell–specific)
Pseudohypoparathyroidism,
McCune-Albright syndrome,
endocrine tumors
Gne (Mnk) Hyposialylation defect, foot process
effacement, GBM splitting,
proteinuria and hematuria
Grhl2 Occasional unilateral renal agenesis,
CD barrier dysfunction, diabetes
insipidus
Autosomal dominant deafness,
ectodermal dysplasia
Ilk Nephrotic syndrome (podocyte-
selective); collecting duct
obstruction (UB-selective)
Insr Podocyte effacement, GBM alteration,
proteinuria (podocyte-selective)
Diabetic nephropathy 658
Itga3 (Integrin α3) Reduced UB branching, glomerular
defects, poor foot process
formation
Itga6 (Integrin α6) Collecting duct dilation and dysplasia Epidermolysis bullosa, collecting
duct dysplasia
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
10.e10 SECTioN i — NoRmAl STRuCTuRE ANd fuNCTioN
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Prkci (aPKCλ/ι) Defect of podocyte foot processes,
nephrotic syndrome (podocyte-
selective)
Ptpro (GLEPP1) Broadened podocyte foot processes
with altered interdigitation patterns
SRNS 657, 680
Rab3A Albuminuria, disorganization of
podocyte foot process structure
Rbpj Decreased renal arterioles, absence
of mesangial cells, and depletion of
renin cells (stromal cell–selective)
Reduction in juxtaglomerular cells,
impaired renin synthesis (renin
cell–selective)
Loss of principal CD cells
(UB-specific)
Rhpn1 FSGS, podocyte foot process
effacement, GBM thickening
Robo2 Abnormal pattern of podocyte foot
process interdigitation, focal
effacement of foot processes,
proteinuria
CAKUT, VUR 682
Scl5a2 (SGLT2) Elevated urinary excretion of glucose,
calcium, and magnesium
Glucosuria 683
Sh3gl1, Sh3gl2, Sh3gl
(Endophilin 1/2/3)
Podocyte foot process effacement
and proteinuria, neuronal defects
Sirpa Irregular podocyte foot process
interdigitation, mild proteinuria
Sox4 Oligonephronia, podocyte effacement,
GBM defects (MM-selective)
Sox17, Sox18 Vascular insufficiency in kidneys and
liver; ischemic atrophy of renal and
hepatic parenchyma; defective
postnatal a
HLT (hypotrichosis-lymphedema-
telangiectasia) syndrome (hair,
vascular, and lymphatic disorder)
Sv2b Podocyte foot process effacement
and proteinuria
Synj1 Podocyte foot process effacement
and proteinuria; neuronal defects
Tcf21 (Pod1) Lung and cardiac defects, sex reversal
and gonadal dysgenesis, vascular
defects, disruption in UB branching,
impaired podocyte differentiation,
dilated glomerular capillary, poor
mesangial migration
Tek (Tie2) Loss of ascending vasa recta and
medullary capillary plexus, urinary
concentration defects
Cutaneous and mucosal venous
malformations, congenital
glaucoma
Tfcp2l1 Loss of CD intercalated cells 273
Tjp1 (ZO-1) Podocyte effacement and proteinuria 687
Trp63 (TP63) Loss of CD intercalated cells ADULT (acro-dermato-ungual-
lacrimal-tooth) syndrome;
limb-mammary syndrome
Trpc6 Protected from angiotensin-mediated
or proteinuria or complement-
dependent glomerular injury (null
mutation); podocyte foot process
effacement and proteinuria
(transgenic overexpression in the
podocyte lineage)
SRNS, FSGS 460, 489, 490,
Vangl2 Immature and poorly branched
glomerular tuft
Neural tube defects 332
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
CHAPTER 1 — EmbRyology of THE KidNEy 10.e
Gene Mutation or
Knockout Phenotype Associated Human Diseases References
Vegfa Endotheliosis, disruption of glomerular
filtration barrier formation, nephrotic
syndrome (podocyte-selective);
peritubular capillary rarefaction and
polycythemia (tubule-specific)
Vhl Glomerulonephritis
(podocyte-selective)
Von Hippel-Lindau syndrome 400
Wasl (N-wasp) Podocyte effacement, proteinuria 693
Wnt7b Impaired development medullary
microvasculature
Wnt11 Glomerular cysts 695
ADPKD, Autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; CAKUT, congenital
anomalies of the kidney and urinary tract; CD, collecting duct; CM, cap mesenchyme; FSGS, focal segmental glomerulosclerosis;
GBM, glomerular basement membrane; GDNF, glial cell–derived neurotrophic factor; MM, metanephric mesenchyme; SRNS, steroid-
resistant nephrotic syndrome; UB, ureteric bud; VUR, vesicoureteral reflux_._
Table e1.2 Summary of Knockout and Transgenic Models for Kidney Development (Cont’d)
