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Bio 108 - 3/17/2000 Molecular Genetics of Pattern Formation III • Contact information office hours W/F 3-4 phone 824-8573 [email protected] (preferred contact mode) • Lectures posted at http://blumberg-serv.bio.uci.edu/bio108-w2000/index.htm http://blumberg.bio.uci.edu/labtemp/bio108-w2000/index.htm • Exam update – Dr. Cho and I will write the exam. – Questions will be approximately equally distributed between the sections each of us taught – The examination will not be identical to any given in previous years BioSci 108 lecture 28 (Blumberg) page 1 ©copyright Bruce Blumberg 2000. All rights reserved Homeotic selector genes specify segment identity • • Hierarchy – maternal egg polarity genes divide the embryo into broad regions anterior/posterior, dorsal/ventral – gap genes respond to this information and divide the embryo into smaller domains along the A/P axis – pair-rule genes respond to the gap genes by being expressed in 7 stripes along the A/P axis – segment-polarity genes respond to the pair-rule genes by subdividing the embryo into 14 parasegments, each of which contains 3 compartments. – Homeotic selector genes interpret the pattern created by the actions and interactions of the egg polarity, gap, pair-rule and segment-polarity genes to create unique anteroposterior positional codes for each compartment of the embryo Drosophila has two clusters of homeotic selector genes – antennapedia and bithorax complexes – most other invertebrates and insects have a single complex that contains both antennapedia and bithorax complexes • can think of antp and bx complexes as the two halves of HOM-C – The invertebrate complex is collectively referred to as HOM-C. The correxponding complexes in vertebrates are called the HOX-C BioSci 108 lecture 28 (Blumberg) page 2 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • • Homeotic selector genes have precise domains of action – like the pair-rule genes, the domain of action is the parasegment (Fig 21-50) – homeotic genes have precise expression boundaries, but these are typically only at either the anterior or posterior – mutations are dramatic -> antp (Fig 21-67) homeotic selector genes are recessive lethal – embryos typically do not survive beyond hatching of the egg into a first instar larva – practically speaking, this means that one must evaluate such mutations at ~24 hours or so (just when the larva would ordinarily hatch – clear view of what is happening (Fig 21-68) – larvae deficient in the entire bithorax complex are particularly interesting. • All of the parasegments posterior to P5 take on the character of P5 • P5 is T2/3 • these flies consist of a head,T1 and then 11 segments which look more or less like T2 • T2 has a pair of wings and a pair of legs – ancestral “ground state” – essential role of homeotic selector genes is to define the differences among parasegments • loss of gene function = loss of differences BioSci 108 lecture 28 (Blumberg) page 3 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • • Homeotic selector genes are molecular address labels – first activated at cellular blastoderm – all of HOM-C genes are cloned and expression patterns have been analyzed – to a first approximation, the anterior border of each gene coincides with the regions that develop abnormally in loss-of-function mutations – this implies that these genes encode molecular address labels for each cell • if the address labels are changed, the cells behave as if they are somewhere else – expression patterns of HOM-C genes coincides with parasegmental boundaries established by segmentation genes • combination of HOM-C and segmentation gene products defines a unique address for cells in one subdivision of one segment Homeotic selector genes are the “keepers” of positional information – all homeotic selector genes are transcription factors – all contain a highly conserved DNA sequence called the “homeobox” – the homeobox encodes a segment of the protein called the “homeodomain” • homeoboxes were first identified in homeotic selector genes, hence the name BioSci 108 lecture 28 (Blumberg) page 4 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • Homeotic selector genes and positional information (contd) – together the antennapedia and bithorax complexes contain 8 genes (the HOM-C) • these are very large transcription units (more than 300 kilobases each) • these large transcription units contain a large number of regulatory elements that control the temporal and spatial expression of the genes • these regulatory elements contain binding sites for the products of egg polarity and segmentation genes – this is the molecular mechanism underlying the combinatorial regulation elicited by these genes – these binding sites are the interpreters of positional information BioSci 108 lecture 28 (Blumberg) page 5 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • Position of genes within the complex corresponds to the regions of expression along the A/P axis (Fig 21-69) – order of genes is invariant across species – all genes are transcribed in the same direction – most proximal genes are expressed in the anterior, more distal genes are expressed in the posterior – appears that the genes are serially activated by an unknown process that spreads along the chromosome – most of the genes have unique 5’ borders • but the expression domains can overlap posteriorly • it turns out that the proteins are expresses in a more restricted pattern than the mRNAs – overlapping expression patterns means more genes are expressed in the posterior – this leads to predictions about the effects of mutations • loss-of-function -> anterior transformations • gain-of-function -> posterior transformations – questions remaining: • why is direction of transcription the same? • why is order conserved? – accident or design? • why are inversions and rearrangements not tolerated? BioSci 108 lecture 28 (Blumberg) page 6 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • There are not enough HOM-C genes for all parasegments – only 8 HOM-C genes but 14 parasegments – bithorax complex contains only 3 genes but is responsible for the differences among 10 parasegments – many of Bx-C mutations affect only a single segment or part of a segment • map along the chromosome in the order of expression • most map to noncoding regions of DNA, putative regulatory sequences – suggests that differences between body regions are defined not only by the presence of homeotic gene products but by persistent differences in states of the control regions • implies that control regions are not simple on-off switches but integrate the signals received in a complex way BioSci 108 lecture 28 (Blumberg) page 7 ©copyright Bruce Blumberg 2000. All rights reserved HOM-C (contd) • What is the mechanism that retains positional memory? – one good mechanism is positive feedback • once a gene product is expressed, it stimulates its own expression • many HOM-C genes have autoregulatory binding sites in their promoters – but positive feedback, in itself, is insufficient to maintain memory without other factors – another group of genes, the Polycomb group, are required to repress homeotic selector genes that should not be expressed in a particular region • loss-of-function mutations result in indiscriminate upregulation of HOM-C genes all over the embryo • polycomb is bound to the chromatin of the genes it controls – genes related to polycomb appear to be involved in the control of chromatin structure • this suggests that persistent modifications in chromatin structure can also have an important role in positional memory BioSci 108 lecture 28 (Blumberg) page 8 ©copyright Bruce Blumberg 2000. All rights reserved HOX-C • • • Vertebrates have homologous developmental control genes to invertebrates – homologous means derived from a common ancestor – when Drosophila homeobox genes were identified, researchers screened for homologs in vertebrates – an important point to remember is that although not all developmental mechanisms are conserved, the genes employed to control development are the same across species. • e.g. bicoid and goosecoid • dpp and BMP-4 – the vertebrate homologs of the HOM-C are called HOX-C Genes homologous to HOM-C are found in all organisms that have been examined – C. elegans – Hydra – they are invariably grouped into complexes that maintain the order and direction of transcription HOX-C and HOM-C complexes contain very similar genes (Fig 21-80) – similar (paralogous) genes occupy the same position in each complex! – this suggests that the HOM-C(HOX-C) complex was invented very early in evolution retained • retained and used with only few changes BioSci 108 lecture 28 (Blumberg) page 9 ©copyright Bruce Blumberg 2000. All rights reserved HOX-C (contd) • • • Expression of HOX-C genes is highly ordered along the A/P axis (Fig 21-81) – most clearly seen in the developing neural tube – A/P position mirrors position in the complex Gene expression domains draws parallels between the body parts of insects and vertebrates (fig 21-82) – stop and think about this for a minute - the genes that specify head in Drosophila are the same genes that pattern your head • e.g. labial and HOX-A,B,D-1 genes – as in Drosophila compartments, the regions specified by HOX-C genes do not cross compartment boundaries – clearest example is in the vertebrate hindbrain • segments are called rhombomeres • lateral to rhombomeres are the branchial arches – one branchial arch/two rhombomeres Vertebrates have four HOX-C complexes – two genome duplications in the vertebrate lineage • four complexes are organized like HOM-C – some genes may be lost in one complex – additional internal duplications have occurred » paralog 3 genes and dfd » paralog 10-13 and AbdB BioSci 108 lecture 28 (Blumberg) page 10 ©copyright Bruce Blumberg 2000. All rights reserved HOX-C (contd) • HOX-C genes specify a discrete combinatorial code that uniquely identified each cell in the body – called the HOX code – alterations in the HOX code cause predictable changes in patterning • loss-of-function cause anterior transformations • gain-of-function cause posterior transformations – since there are multiple copies of each HOM-C gene, it is difficult to obtain perfect homeotic transformations • important concept: functional redundancy • this means that the if one gene is knocked out, the remaining paralogous genes can partially compensate – HOX-C and HOM-C genes bind to the same target DNA sequence • suggests that differences in affinity may be an important factor in regulation • also suggests that the genes may be functionally redundant • vertebrate HOX genes can rescue Drosophila homeotic mutations – best proof of conserved function – this is also a good justification for studying simpler model organisms that only have a single gene at each position in the complex BioSci 108 lecture 28 (Blumberg) page 11 ©copyright Bruce Blumberg 2000. All rights reserved Final comments • • You may have noticed that prices at the UCI bookstore are not especially good. – in fact, the bookstore marks items up by a fixed amount (26%) over cost – the very frequent result is that books cost MORE than the publisher’s list price – what can you do? • buy your books direct from the publisher online • buy your books from an online discount bookstore • but be careful about edition numbers – a good resource is http://www.bestbookbuys.com/ • this site has a search engine that compares prices and availability of a book among many booksellers. some students are not happy with the selection of upper division satellite courses required – one solution is to complain to the Dean, Susan Bryant – another possibility is to take graduate courses. Most of these are open to undergraduates who have completed the core and a few other satellites. • feel free to ask the instructor BioSci 108 lecture 28 (Blumberg) page 12 ©copyright Bruce Blumberg 2000. All rights reserved