Lecture 3: Digestive and Urogenital System Key Facts Digestive and respiratory system - Endoderm: produces signals that

direct formation of the notochord, circulatory system and mesodermal layer. Forms the linings of the digestive tube and respiratory tube - The connection between the anterior endodermal portion of the digestive and respiratory tubes form the pharynx - Pharynx: the mammal produces four pairs of pharyngeal pouches and between them are the pharyngeal arches. - Lungs: In the center of the pharyngeal floor, between the fourth pair of pharyngeal pouches, the laryngotracheal groove extends ventrally; this then bifurcates into branches that form paired bronchi and lungs. Laryngotracheal endoderm becomes the lining of the trachea, and two bronchi, and alveoli. - There are two ways that digestive tube is specified: internal gradients and signaling with the lateral plate mesenchyme. - Liver formation: ectoderm and notochord block the ability of endoderm to express hepatic (liver) specific genes. But, when it comes in contact with cardiogenic mesoderm, liver specific genes are promoted. - Pancreas formation: Pdx1 is important to initiate budding from the gut epithelium and repressing genes that characterize other regions. Pdx1 is expressed only in regions where gut tube is in contact with Aorta and vitelline veins. Only the right Vitelline veins survive causing right side to have pancreas. Urogenital system - develops from the intermediate mesoderm - Mammalian kidneys form in three stages, where first two are transient, and last one forms a mature functional kidney: pronephros, Mesonephros, Metanephros. - The ureteric bud and metanephrogenic mesenchyme interact and induce each other to form kidney. The metanephrogenic mesenchyme causes the ureteric bud to elongate and branch. These branches induce the loose mesenchymal cells to form epithelium aggregation. Each epithelium differentiates into a nephron. - Specification of metanephric mesenchyme requires a number of transcription factors like Fox family, Hoxa, Hoxc, & Hoxd. WT1, FGF2 and BMP7 secreted by uretic bud prevents apoptosis of mesenchymal cells - Factors from uretic bud induce mesenchymal cells to condense and form epithelial cells like FGF2 & BMP7, leukemia inhibitory factor (LIF), Wnt family, Lim 1 Key Concepts Digestive and respiratory system - Digestive tube extends the length of the body, and also buds to form liver, gallbladder, and pancreas - Respiratory tube for as outgrowth of the digestive tube and bifurcates into two lungs.

Pharynx: first pharyngeal pouch become tympanic cavity of middle ear and Eustachian tube. The second pouch becomes lymphoid tissue and tonsils. The third pouch becomes part of parathyroid and thymus. The fourth pouch forms rest of parathyroid and postbranchial body. - Wnt signaling (Wnt2 and Wnt2b) is required to form lungs from the digestive tract. They cause accumulation of B-catenis in the region of gut tube that will become lung and trachea. In a Wnt 2 and 2b KO fails to form the lungs, while ectopic expression of B-catenin will cause extra lung to form. - The digestive tube differentiation is specified with FGF and Retinoic Acid gradients. Pharynx develops where there is little or no retinoic acid; higher levels specify the pdx1 gene that differentiates duodenum, pancreas and liver; cSox2 gnene that specifies stomach and esophagus. Even higher levels induce CdxC and A which specify small and large intestines. - Ass the digestive tube meets different mesenchyme, the mesenchyme instructs the tube to differentate into different type of gut. Ex: Wnt activation leads to intestine epithelium, and no Wnt leads to stomach epithelium. But, as the gut differentiates, it induces splanchnic mesoderm to become regionally specific though Shh. Urogenital system - Pronephic duct forms from intermediate mesoderm, which then migrates caudally. The anterior part of duct induces mesenchyme to form pronephric tubules. Most of these tubules undergo apoptosis except for Wolfian duct which differentiates to create important parts of the excretory system. - Wolffian duct induces mesonephros tubules to form from adjacent mesenchyme. As posterior tubules form anterior ones (pronephic) begin to regress. In mammels these mesonephros form tubules to transport sperm from testes to urethra. - Metanephros forms in the posterior part of mesenchyme inducing branching of nephric ducts. Uretic buds form ureters and collecting duct. Uretic buds induce formation of nephrons from the adjacent mesenchymal cells. - Fox Family: Hoxb4 positively regulates the metanephrogenic mesenchyme and Foxc1 and Foxc2 negatively regulates metanephrogenic mesenchyme. Foxc1/Foxc2 double mutant have extra ureters, kidneys and other renal structures. - Hox11 genes regulate mesenchymal differentiation, when ablated causes differentiation to arrest because mesenchyme cannot induce ureteric buds to form. The mesenchyme responses to ureteric buds because of WT1, without which the metanephric mesenchyme cells undergo apoptosis. - GDNF secretion by mesenchyme is limited to the posterior region where epithelial buds would form. Branching of uretic bud is effected by GDNF, WT1, TGFB1, BMP4, and collagen XVIII. GDNF can induce secondary buds. TGF-B1 prevents further branching, and stabilizes formed branches. BMP4 restricts branching to appropriate sites. collagen XVIII is only found on branches not at tips, thus also function in restricting branching. - Wnt9B and Wnt6 from the ureteric bud induce mesenchyme cells to aggregate by inducing expression of E cadherin. Wnt 4 converts aggregated mesenchyme

into nephrons. In mice without Wnt4 the mesenchyme aggregates but does not form epithelium. Lim 1 is expressed in newly aggregated mesenchyme and in developing nephron, thus may be critical to nephron development. TGFb1 regulates branch formation, by preventing extra branches from forming. Exogenous expression of TGFb1 shows the epithelium is prevented from branching.

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