Development Of Kidney-Bladder-Suprarenal Gland Notes PDF

Development of the Kidney, Urinary bladder and Suprarenal gland Page 1 of 20 Dennis J. Goebel, Ph.D. Lecture Objectives: 1. Describe the development of the urinary system. 1.1 Describe the three embryonic stages of kidney formation....

Development of the Kidney, Urinary bladder and Suprarenal gland Page 1 of 20 Dennis J. Goebel, Ph.D. Lecture Objectives: 1. Describe the development of the urinary system. 1.1 Describe the three embryonic stages of kidney formation. 1.2 Describe the timing and regional expression of the pronephric kidney and duct formation. 1.3 Describe the timing and regional expression of the mesonephric kidney and duct system. 1.4 Describe the formation of the glomerulus and the glomerular capsule in the formation of the functioning nephron 1.5 Define the components of the renal corpuscle of the mesonephric kidney 1.6 Describe the fate of the mesonephric duct in the male and female. 1.7 Describe the regional expression and timing of the formation of the metanephric kidney and duct system. 1.8 Describe the ureteric bud and its association with the mesonephric duct and neighboring mesoderm. 1.9 Know the derivatives formed by the ureteric bud and how the major, minor calyces and the collecting ducts are formed. 1.10 Understand how the metanephric mesoderm forms metanephric blastemas and their association with the invading collecting ducts. 1.11 Describe the fate of the renal vesicle and its differentiation into a nephron. 1.12 Describe the components of the formed metanephric nephron. 1.13 Describe the formation of the glomerulus in the metanephric kidney. 1.14 Describe ascent of the metanephric kidneys and the repositioning of the renal artery during this process 1.15 Understand the basic molecular signaling events between the ureteric bud and the metanephric mesoderm required for the formation of the collecting duct system, the condensation of the metanephric caps and the induction of tubule formation of the nephron. 1.16 Describe embryonic source and the formation of the renal pelvis and the ureter of the metanephric kidney. 1.17 Describe the embryonic source and formation of the urinary bladder. 1.18 Understand the contribution made by the distal end of the mesonephric duct to the formation of the trigone of the urinary bladder and how this in turn links the right and left ureters into the bladder. 1.19 Review the formation of the urogenital sinus and the anal rectal canal from the cloaca. 1.20 Describe the fate of the three regions of the allantois in the formation of the urinary bladder, the urachus and the pelvic part of the urogenital sinus. 2. Describe the development of the suprarenal glands. 2.1 Describe the germ layer sources for formation of the formation of the suprarenal cortex and medulla. 2.2 Describe the formation of the primitive cortex of the suprarenal gland. 2.3 Describe the formation of the definitive cortex and the fate of the primitive cortex following this process. 2.4 Know the source for the three layers of the differentiated suprarenal cortex. 2.5 Describe the germ source and formation of the suprarenal medulla. Development of the Kidney, Urinary bladder and Suprarenal gland Page 2 of 20 Dennis J. Goebel, Ph.D. 2.6 Know that the chromaffin cells of the suprarenal medulla are under the influence of the sympathetic autonomic nervous system and respond identically to post-ganglionic second-order neurons located in sympathetic ganglion by releasing norepinephrine. Development of the Kidney, Urinary bladder and Suprarenal gland Page 3 of 20 Dennis J. Goebel, Ph.D. Lecture Outline I. Development of the kidney A. Overview B. Pronephros system 1. Transiently expressed during 4th week of development 2. Formation of the right and left mesonephric ducts. 3. Nonfunctioning nephotome 4. Pronephric duct degenerates entering the Mesonephros stage of kidney C. Mesonephros system 1. Transiently expressed during week 4-6 of development 2. Formation of the right & left pronephric duct from intermediate mesoderm a. Signaling causes the neighboring intermediate mesoderm to become segmented in this region. 3. Somite segmentation in the thoracic, and upper lumbar region initiates the induction of a right and left excretory tubule pre segment. a. Maturation of the excretory tubule, induction of the glomerulus and bowman’s capsule. 4. Degeneration of the mesonephric kidney and the mesonephric duct occurs in a rostral caudal direction upon the signaling of the formation of the metanephrose system during the 5th week of development. a. In the male, the distal mesonephric duct does not fully degenerate and will aid in the formation of genital ducts. D. Metanephros system (permanent kidney): Overview 1. Metanephric mesoderm development of the metanephric kidney 2. Role of the ureteric bud a. Relationship of the ureteric bud with the metanephric mesoderm. b. Ureteric bud formation of the renal pelvis and major calyces. c. Divisions of the major calyces i. Minor calyces ii. Collecting tubules iii. Summary 3. Formation of the nephron in the metanephric kidney a. Formation of the metanephric caps around the terminal distal tubules. i. Differentiation of the distal tubule into Bowman’s capsule, induction of the formation of the glomerulus and the formation of a nephron. ii. Connection of the distal convoluted tubule to the collecting duct iii. Functional nephron formation period week 10- newborn. 4. Molecular regulation of the development of the permanent kidney. a. Role of WT1 release by the metanephric mesoderm. in the formation of the metanephric caps. Development of the Kidney, Urinary bladder and Suprarenal gland Page 4 of 20 Dennis J. Goebel, Ph.D. E. Ascent of the kidney from the pelvis to the lumbar-thoracic region of the posterior abdominal wall. 1. Factors important for the ascent of the kidney a. Diminished body curvature with the development of the embryo/fetus. b. Increased growth and elongation of the lumbar and sacral regions. 2. Fixation of the kidneys in their adult position. 3. Blood arterial and venous supply to the kidney F. Development of the ureter and bladder 1. Role of the ureteric bud and mesonephric duct in the attachment of the ureter to the developing bladder. a. Early development: Relationship of the developing ureter with the mesonephric duct and the developing urogenital sinus. b. Incorporation of the mesonephric duct and the right and left ureter into the developing bladder and the formation of the trigone of the bladder. c. Origin of the endothelial lining of the ureter 2. Formation of the urinary bladder a. Early stage development of the urogenital sinus from the allantois b. Anorectal septum division of the cloaca into the urogenital sinus and the anorectal canal. i. Fate of the terminal part of the allantois ii. Fate of the mid-part of the allantois iii. Fate of the pelvic part of the urogenital sinus in male & female. II. Development of the suprarenal glands A. Overview of the formation of the adrenal cortex and the adrenal medulla 1. Formation of the primitive (or fetal) acidophilic mass of the adrenal cortex. a. Addition of the layers contributing to the formation of the definitive adrenal cortex layers of zona glomerulosa and zona fasciculata. b. Maturation of the fetal cortex into the zona reticularis 2. Origin and formation of the adrenal medulla a. Migration of neural crest cells forming chromaffin cell cords Development of the Kidney, Urinary bladder and Suprarenal gland Page 5 of 20 Dennis J. Goebel, Ph.D. DEVELOPMENT OF THE KIDNEY,URINARY BLADDER AND SUPRARENAL GLAND I. DEVELOPMENT OF THE KIDNEY A. OVERVIEW: The formation and development of the kidney system is derived from intermediate mesoderm, which migrates bilaterally to a region on the developing dorsal body wall that will form the urogenital ridge. The intermediate mesoderm will contribute to both kidney (responsible in forming nephrogenic cords) and gonadal development. In developing embryo, the intermediate mesoderm signals an overlapping succession of three independent kidney systems, which begins with the most primitive system (Pronephros kidney system), then advances to the intermediate system (Mesonephros kidney system) and finally leads to the signaling of the formation of the permanent (advanced) kidney (defined as the Metanephros kidney system). B. First stage: The Pronephros system (primitive kidney): 1. Is transiently expressed during the 4th week of development. 2. Molecular signaling of this primitive kidney system causes the formation of a right and left pronephric duct from the intermediate mesoderm located in the cervical region of the developing embryo. a. This signaling causes the neighboring intermediate mesoderm to become segmented in this region (see Figure 1). Figure 1: Sadler Development of the Kidney, Urinary bladder and Suprarenal gland Page 6 of 20 Dennis J. Goebel, Ph.D. 3. The pronephros system never forms a functioning nephotome. 4. The pronephric duct and the intermediate mesoderm associated with the ducts completely disappear upon the initiation of the Mesonephros stage. C. Second stage: The Mesonephros system: 1. The mesonephric kidney forms a functional excretory system in a region of the intermediate mesoderm. a. It is positioned between upper thoracic and mid lumbar segments. b. Forms during weeks 4-6. 2. The mesonephric kidney is centered about the formation of the right and left mesonephric ducts, and empties into the forming urogenital sinus within the cloaca (see Figure 1 on previous page). 3. The somite segmentation of the thoracic and upper lumbar region initiates the induction of segmented excretory tubules (one pair per somite) that extend off of the mesonephric duct. a. The excretory tubules elongate and form an S- shaped loop (see Figure 2 on the next page). The terminal end of the tubule will then acquire (through a reciprocal signaling mechanism) a tuft of capillaries, from the neighboring dorsal aorta, that will form a relatively large glomerulus at their medial extremity. This in turn stimulates the neighboring region of the excretory tubule to form a C-shaped capsule surrounding the glomerulus forming a Bowman’s capsule (see Figure 2 on the next page). i. By definition: a glomerulus surrounded by a Bowman’s capsule is called a renal corpuscle (see Figure 3 on the next page). Development of the Kidney, Urinary bladder and Suprarenal gland Page 7 of 20 Dennis J. Goebel, Ph.D. Figure 2: Moore 12-5 E&F 4. Mesonephric kidney function begins to degenerate during week 5, in a rostral-caudal direction, upon the signaling of the formation of the metanephros kidney. Figure 3: Sadler 16-3 5. It is important to note here, that although the mesonephric kidney’s function is transient, the distal portion of the Development of the Kidney, Urinary bladder and Suprarenal gland Page 8 of 20 Dennis J. Goebel, Ph.D. mesonephric duct that empties into the cloaca remains in both the male and female, and will serve as the origin for the development of the metanephric kidney. In addition, in the male, the distal portion of the mesonephric duct will aid in the development of the genital ducts (more on this later in these notes). D. The metanephros system (the third stage) overview: gives rise to the permanent kidneys and begins forming in the pelvis, during the 5th week of development. 1. The metanephric kidney forms from the intermediate mesoderm (called metanephric mesoderm) located in the lower lumbar-sacral region, however, the duct system differs from the first two systems in that they develop from an out pocketing of the distal right and left mesonephric ducts (near the entrance of the cloaca). This out-pocketing is called the ureteric bud (see Sadler Figure 1A &B on page 5 of my notes). 2. The ureteric bud and the development of the collecting system of the metanephric kidney: a. The ureteric bud penetrates the metanephric mesoderm and becomes “capped” by it anteriorly, posteriorly, superiorly, inferiorly and laterally. Note it is not capped medially, as this region will become the hilus of the kidney. b. The ureteric bud then will dilate to form the renal pelvis and then give rise to 3 primary branches that will form the future major calyces (see Figure 4B). Figure 4: Sadler Development of the Kidney, Urinary bladder and Suprarenal gland Page 9 of 20 Dennis J. Goebel, Ph.D. c. Each of the major calyces forms two new buds that penetrate further into the metanephric mesoderm. These branches will further subdivide into tubules approximately 12 times (see Figure 4C &D on previous page). i. Minor calyces are formed by the consolidation of the third and fourth subdivisions. ii. All of the distal divisions (5-12) will form the collecting tubules system of the kidney and will converge upon the corresponding minor calyces. iii. A staggering fact is that each ureteric bud gives rise to the ureter, the renal pelvis, the 2-3 major calyces, 15-18 minor calyces and over 1million collecting tubules. 3. The excretory system of the metanephric kidney and the formation of the nephron are derived from a condensation of metanephric mesoderm (Now called the Metanephric caps) surrounding the invading collecting ducts. a. Each collecting tubule is covered at its distal end by a metanephric tissue cap. Under inductive influences by the tubule cells, the metanephric mesoderm will condense and form renal vesicles (see Figure 5 A&B on the next page). i. Each renal vesicle then develops into a small S-shaped tubule. Capillaries will approach the distal surface of the renal vesicle and develop into a glomerulus, while the proximal end will attach to the collecting tubule and give rise the following structures from proximal-distal: The distal convoluted tubule, descending and ascending limbs of Henel’s loop, proximal convoluted tubule and terminating as Bowman’s capsule (See Figure 5C-F). Development of the Kidney, Urinary bladder and Suprarenal gland Page 10 of 20 Dennis J. Goebel, Ph.D. Collectively, these bolded structures, together with the glomerulus, define a functional filtration unit called a nephron. ii. The distal convoluted tubule will form an open connection to the collecting tubule. At this time period (~10th week gestation), urine production begins. iii. Nephrons continue to form until birth, yielding an estimate of ~ 1 million nephrons per kidney. iv. At birth the kidneys are lobulated, however this appearance will disappear as the result of further growth of the nephrons. Figure 5: Sadler 16.6 4. Molecular regulation of the development of the permanent kidney: As has been shown elsewhere, differentiation of the kidney involves reciprocal molecular interactions between the epithelium of the ureteric bud and the metanephric mesoderm (MM). Development of the Kidney, Urinary bladder and Suprarenal gland Page 11 of 20 Dennis J. Goebel, Ph.D. a. Key to kidney formation is the release of WT1 from the MM. This makes the mesenchyme receptive to induction signaling by the ureteric bud. i. WT1 causes local release of glial-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) by the mesenchyme. GDNF and HGF both stimulate the epithelium of the collecting tubule to release fibroblast growth factor 2 (FGF2) from neighboring the collecting tubule (from the ureteric bud: see Figure 6A). FGF2 blocks apoptosis and stimulates cell proliferation of the local metanephric mesenchyme, and maintains continued release of WT1 by the neighboring mesenchyme. ii. Key to tubule formation of the nephron is the release of the transcription factor WNT9B and WNT6 from the ureteric bud. This causes the upregulation of PAX2 and WNT4 by the neighboring mesenchyme, and promotes the condensation of the neighboring mesenchyme, to initiate tubule formation (see Figure 6). Figure 6: Sadler 16.7 Development of the Kidney, Urinary bladder and Suprarenal gland Page 12 of 20 Dennis J. Goebel, Ph.D. E. Ascent of the kidney: The metanephric kidney initially forms within the pelvic region of the developing embryo. 1. The ascent of the kidney from the pelvic region, to its final position in the abdominal cavity, results from the following. a. Diminishing body curvature of the embryo, as a function of growth/development. b. Increased growth and elongation of the lumbar sacral regions. 2. The kidneys become fixed in place when they come in contact with the developing suprarenal glands (to be described later in these notes). 3. Blood supply to the kidney: Initially, the kidneys receive their blood supply from a branch of the common iliac arteries and veins. As the body of the embryo elongates, the kidneys ascend and receive new branches from the aorta/ inferior vena cava, in route to their final positions (see Figure 7). Figure 7: Moore 12- Development of the Kidney, Urinary bladder and Suprarenal gland Page 13 of 20 Dennis J. Goebel, Ph.D. a. In most cases, the caudal arterial and venous supply to the kidneys is signaled to regress and degenerate, as the newer cranial branches become established (See Figure 7 on previous page). b. Note: The renal veins are usually positioned anterior to the renal arteries. F. The development of the Ureter and Bladder 1. The formation of the ureter begins at the base of the ureteric bud. a. Initially the ureter comes off of the distal portion of the mesonephric duct (see Figure 8A) in both male and female, which in turn, empties into the forming urogenital sinus. Figure 8: Sadler 16.12 b. During differentiation of the cloaca, the caudal portion of the right & left mesonephric ducts are absorbed into the wall of the developing urinary bladder. Note that each ureter now directly enters the wall of the posterior bladder separately (see Figure 8C). The portion of the mesonephric duct that is absorbed into the bladder becomes the trigone of the urinary bladder (see Figure 9C & D on the next page). Development of the Kidney, Urinary bladder and Suprarenal gland Page 14 of 20 Dennis J. Goebel, Ph.D. c. Note that the ureteric bud and the mesonephric ducts are both derived from intermediate mesoderm and that, the mucosal linings of both the trigone and the ureter lack an endodermal lining. Over time, the mesothelial lining of the bladder is replaced by the epithelium covering the allantois and cloaca (which is derived from endoderm). Figure 9: Sadler 16.14 2. Formation of the urinary bladder: a. Recall that initially the urogenital sinus (formed from the allantois) and the anorectal canal (derived from the hindgut) are in communication with each other in the region of the cloaca (see Figure 10A&B). By week 5, the urorectal septum begins to partition the cloaca and by week 7, it separates it into an anterior urogenital sinus and a posterior anorectal canal (Figure 10C). Figure 10: Sadler 15.36 Development of the Kidney, Urinary bladder and Suprarenal gland Page 15 of 20 Dennis J. Goebel, Ph.D. b. By the 8th week, complete separation of the anorectal canal and the urogenital sinus by the ingrowth of the urorectal septum has occurred (see Figure 10 on previous page). i. The terminal part of the allantois extending to the umbilical region of the fetus) forms a thick fibrous cord called the urachus (also known as the median umbilical ligament). This ligament remains connected to the apex of the urinary bladder and extends to the umbilicus at midline on the internal surface of the anterior abdominal wall. ii. The proximal portion of the allantois forms the primitive urogenital sinus, which will give rise to the urinary bladder iii. The narrowed portion of the urogenital sinus, at the base of the bladder, gives rise to the pelvic part of the urogenital sinus (see Figure 11A & B), which in the male, gives rise to the prostatic and membranous part of the urethra and in the female, the membranous urethra only. a. In the male, the terminal part of the urogenital sinus will give rise to the penile urethra (this will be expanded in the next Unit). Figure 11: Sadler 16.13 Development of the Kidney, Urinary bladder and Suprarenal gland Page 16 of 20 Dennis J. Goebel, Ph.D. b. In the male, the epithelium of the urethra (from the pelvic portion of the urogenital sinus) just below the neck of the bladder proliferates and forms a number of outgrowths into the surrounding mesenchyme (see Figure 11B on previous page). Induction between the two germ layers results in the formation of the prostate gland. Details will be presented in a later unit. II. Development of the suprarenal glands (adrenal glands): A. The suprarenal glands (adrenal glands) begin forming during the 6th week of development and are derived from two germ-layer sources. 1. The adrenal cortex is derived from axillary mesothelial cells associated with the root of the dorsal mesentery, which also forms the developing gonads (to be described in a later presentation). These cells proliferate and penetrate the underlying mesenchyme and give rise to a large aggregation of acidophilic cells that form the C-shaped fetal cortex (also called the primitive adrenal cortex) of the suprarenal gland (see Figure 12A). a. Shortly after the formation of the primitive cortex, a second wave of mesothelium surrounds the acidophilic mass. These cells form the definitive cortex of the gland (e.g. will give rise to the zona glomerulosa and the zona fasciculata of the adrenal cortex). See Figure 12B. b. After birth most of the fetal cortex (acidophil cells) degenerate, while the outermost layers, consisting of cells which from the zona glomerulosa and zona fasciculate are retained. See Figure 12B on next page. c. The adrenal medulla has its origin from neural crest cells (which migrate from the region that will form the sympathetic chain ganglion). These cells Development of the Kidney, Urinary bladder and Suprarenal gland Page 17 of 20 Dennis J. Goebel, Ph.D. enter the cavity created by the forming adrenal cortex medially (see Figure 12A) and from the medulla of the developing suprarenal gland (see Figure 12B). Figure 12: Sadler 18.43 i. The neural crest cells will rearrange into cords and clusters within the medulla to become the chromaffin cells of the adrenal medulla. These cells synthesize and release noradrenalin under the control of preganglionic sympathetic input from the greater splanchnic nerve (covered in Gross Anatomy). ii. Note that the suprarenal medulla functions identically to second-order neurons associated with all sympathetic autonomic ganglia (e.g. releases norepinephrine). IV. Clinical Relevance: A. Abnormal kidney development 1. Renal Agenesis (Absence of kidney formation). Unilateral renal agenesis occurs in 1:1000 births, with occurrences in males being more prevalent than females. Usually the left kidney is absent, but bilateral cases have been reported. In bilateral renal agenesis (1:3000 births), oligohydramnios Development of the Kidney, Urinary bladder and Suprarenal gland Page 18 of 20 Dennis J. Goebel, Ph.D. (defined as: an abnormally low production of amniotic fluid) occurs, and is incompatible with life. 2. Ectopic kidneys (Abnormal positioning of the kidney(s)): Most ectopic kidneys are located within the pelvis or in the caudal region of the abdomen, as a result of their failure to fully ascend to their final anatomical positions. These kidneys maintain their function and are often associated with more than one renal arterial supply. 3. Horseshoe Kidney (incidence 1/500) involves the fusion of the right and left kidneys at midline. Although renal function is normal and that each side maintains its own blood supply and ureter, their fusion at midline prevents their full assent beyond the inferior mesenteric artery (Figure 13A &B). A B Figure 13 4. Accessory Renal Arteries occur through the assent of the kidney and result in the failure of the more caudal renal branches to degenerate with the establishment of the superior source (See Figure 14A&B). Normally there are no problems with this, however remaining pelvic sources often cross the ureter on the pelvic rim which can impinge upon the ureter and significantly restrict urine flow from the kidney to the bladder. Development of the Kidney, Urinary bladder and Suprarenal gland Page 19 of 20 Dennis J. Goebel, Ph.D. Figure 14 5. Multiple kidneys usually results from a bifurcation of the ureteric bud (See Moore 12-13B & C). Here, each metanephric cap forms an independent ductal system (e.g. separate kidney unit) acquiring its own blood supply and ureter. This can lead several variants including a divided kidney (Moore 12-13B), two kidneys sharing the same ureter (not shown) or two independent kidneys with separate ureters (Figure 15). Figure 15 B. Bladder defects: 1. An urachal fistula occurs as a result of the failure of the intraembryonic portion of the allantois to regress and form the urachus. This will lead to urine draining into the umbilicus (See Figure 16A on the next page). Development of the Kidney, Urinary bladder and Suprarenal gland Page 20 of 20 Dennis J. Goebel, Ph.D. 2. An urachal cyst can occur when a portion of the allantois fails to regress into the median umbilical ligament (See Figure 16B on the next page). 3. The formation of a urachal sinus occurs when the allantois remains open to the umbilicus but is not in communication with the bladder (See Figure 16C). A Sadler 16.15 Figure 16 C. Ectopic openings of the urethra: Although rare, ectopic openings of the ureter in the female have been documented in the posterior wall of the vagina, directly into the urethra (bypassing the bladder), and directly in the vestibule (bypassing the bladder). See Figure 17. Figure 17