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DB10notes - BIOLOGY 205/SECTION 7 DEVELOPMENT LILJEGREN...

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BIOLOGY 205/SECTION 7 DEVELOPMENT- LILJEGREN Lecture 10 The Mouse as a Model for Mammalian Development Since we are mammals, our development is considered the system for which other organisms are "models". 1. Special difficulties of studying mammalian development. a. Development occurs inside mother; post-implantation development cannot be studied in vitro . can only observe embryos up to implantantation in a dish but not beyond. b. Need to form a placenta complicates many early morphological events. c. Life cycles are long (even mice take weeks vs. days for fruit flies and worms). d. Mice relatively expensive to maintain in the lab compared to flies or worms. e. Experimental manipulation of human development not possible due to ethical constraints. 2. A molecular/genetic approach to mammalian development. a. Mouse is the model for mammalian development. For a mammal, has a relatively short life cycle & is relatively small & easy to maintain. Numerous mutations isolated that alter morphology, development, or even behavior. Ie. in Asia where mice were kept as pets and bred for specific traits, mutants were found that twirled around in circles. b. 1970-80s: DNA cloning & sequencing developed. Genes encoding many abundant proteins were identified (but most encoded specialized proteins of differentiated cells, eg. hemoglobin, keratin, muscle actin, myosin, NOT key regulators of development). c. Last 20 years- return to a genetic approach. Forward genetics too hard and expensive in mice (screening for mutants would mean raising 10,000’s of mice—10s of millions of dollars). d. Alternative genetic approaches have paid off: i. Isolation of homologs of Drosophila developmental genes in mammals & realization that previously-cloned mouse genes are homologs of Drosophila genes ii. Isolation of genes encoding classical mouse mutations. (contributed by mouse breeders, spontaneously occuring mutations found in people’s labs) iii. The ability to create mutations in cloned genes and reintroduce them into the mouse (gene knockouts) has revolutionized the study of development in mice. This is a reverse genetic approach, you start with a gene of interest and then examine loss-of- function mutants to determine its function. iv. Creating transgenic mice that express particular genes where they aren’t normally expressed (ie. gain-of-function) also provides valuable information. 3. Creating "knockouts" (making mutations in cloned mouse genes) or gain-of- function mice. a. By far the most exciting recent advantage of the mouse is the ability to manipulate the DNA of the germline in a controlled way. This allows us to
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add or subtract specific genes and study the effects on both development and disease mechanisms. How? b. For years, the only way to make mutations was hard way: Treat mice with mutagens- look at very large numbers of progeny for new mutants. This was very expensive given numbers of mice required. And there wasn’t a way to add a gene in transgenic mice. However, in the late 1980’s mouse molecular biologists dreams came true. The realization of these dreams took
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