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Annotated Classic Protein Control of Pattern Formation

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Annotated Classic Protein Control of Pattern Formation Annotated Classic Protein Control of Pattern Formation James Briscoe1,* 1Developmental Biology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK *Correspondence: [email protected] We are pleased to present a series of Annotated Classics celebrating 40 years of exciting biology in the pages of Cell. This installment revisits “The bicoid Protein Determines Position in the Drosophila Embryo in a Concentration-Dependent Manner” by Wolfgang Driever and Christiane Nüsslein-Volhard. Here, James Briscoe comments on one of a pair of papers from Driever and Nüsslein-Volhard, published back-to-back in Cell, that established bicoid as the first definitive example of a protein morphogen, that is, a protein which shapes a developmental pathway by virtue of its concentration gradient across a region of an embryo. Nüsslein-Volhard shared the Nobel Prize in Physiology or Medicine in 1995 with Edward B. Lewis and Eric F. Wieschaus for their discoveries related to control of early embryogenesis. Each Annotated Classic offers a personal perspective on a groundbreaking Cell paper from a leader in the field with notes on what stood out at the time of first reading and retrospective comments regarding the longer term influence of the work. To see James Briscoe’s thoughts on different parts of the manuscript, just download the PDF and then hover over or double- click the highlighted text and comment boxes. You can also view Briscoe’s annotation by opening the Comments navigation panel in Acrobat. Cell 157, April 24, 2014, 2014 ©2014 Elsevier Inc. Cell, Vol. 54, 95-104, July 1, 1988, Copyright © 1988 by Cell Press The bicoid Protein Determines Position in the Drosophila Embryo in a Concentration-Dependent Manner Wolfgang Driever and Christiane N0sslein-Volhard is established in early embryogenesis. The gradient is of Max-Planck-lnstitut for Entwicklungsbiologie exponential shape and spans the anterior two-thirds of the Abteilung III Genetik egg's length (Driever and N0sslein-Volhard, 1988). Spemannstrasse 35 To assess a correlation between position on the fate 7400 T0bingen, Federal Republic of Germany map and bcd protein concentration, we measured the bcd protein distribution (Driever and N0sslein-Volhard, 1988) in embryos from females homozygous for mutations af- Summary fecting anterior development, as well as in embryos from females with one to four copies of the bcd + gene. We ob- The bicoid (bcd) protein in a Drosophila embryo is de- served a strong correlation between bcd protein concen- rived from an anteriorly localized mRNA and comes to tration and the positions of anterior anlagen on the em- be distributed in an exponential concentration gra- bryonic fate map. We conclude that the bcd protein has dient along the anteroposterior axis. To determine the properties of a morphogen that determines cell fate whether the levels of bcd protein are directly related along the anteroposterior axis in a concentration-depen- to certain cell fates, we manipulated the density and dent manner. distribution of bcd mRNA by genetic means, mea- sured the resultant alterations in height and shape of Results the bcd protein gradient, and correlated the gradient with the fate map of the respective embryos. Increases Fate Map Changes in Mutants Affecting or decreases in bcd protein levels in a given region of the Anterior Pattern the embryo cause a corresponding posterior or an- To determine the relationship between bcd protein levels terior shift of anterior anlagen in the embryo. The bcd and cell fate, we analyzed maternal mutations affecting protein thus has the properties of a morphogen that anterior pattern with respect to their influence on bcd pro- autonomously determines positions in the anterior tein distribution. The cuticle phenotypes of mutations af- half of the embryo. fecting the anterior pattern are shown in Figures 1A-1E. The embryonic fate maps can be readily visualized in the Introduction expression pattern of the zygotic segmentation gene even-skipped (eve; Frasch and Levine, 1987; Figures The polarity and pattern of the Drosophila embryo are de- 1F-1J). termined by a small number of maternal effect genes. By In bcd embryos, the anlagen for the entire anterior em- their phenotypes, three groups of genes may be distin- bryonic half are lacking while the posterior pattern is en- guished that define the anteroposterior pattern in largely larged and spread to the anterior (Figure 1G); the posteri- nonoverlapping domains: the anterior (head and thorax), ormost eve stripe is duplicated at the anterior, reflecting the posterior (abdomen), and the terminal (acron and tel- the duplication of the telson observed in the differentiated son) regions (N0sslein-Volhard et al., 1987). The genes bi- bcd embryos (Figure 1B). In weak bcd mutants, only the cold (bcd), exuperantia (exu), and swallow (swa) are re- anteriormost region is reduced in size while the residual quired for the anterior segmented pattern of head and pattern is spread toward the anterior. thorax (Frohnh0fer and N0sslein-Volhard, 1986, 1987; In exu and swa embryos, the anterior defects are similar Sch0pbach und Wieschaus, 1986; Stephenson and Ma- to those observed in weak bcd mutant embryos (Figures howald, 1987). Several lines of evidence suggest that it is 1C and 1D). However, the region of the thoracic and seg- the bcd gene product that determines anterior pattern. mented head anlagen (parasegments 1-5) is much en- bcd codes for an mRNA localized at the anterior tip of the larged while the posterior pattern (parasegments 6-13) is oocyte and early embryo (Frigerio et al., 1986; Berleth et compressed (Figures 1H and 11; see, for discussion, al., 1988). Variations in the copy number of the wild-type Frohnh0fer and N0sslein-Volhard, 1987). staufen (stau; bcd + gene cause corresponding shifts of anterior pattern Sch0pbach and Wieschaus, 1986; Lehmann and N0ss- elements along the anteroposterior egg axis (Frohnh0fer lein-Volhard, unpublished) embryos display a less severe and N0sslein-Volhard, 1986, 1987; Berleth et al., 1988). reduction of the anteriormost region (Figures 1E and 1J). Cytoplasmic transplantation experiments reveal a long- stau embryos have reduced levels of transplantable bcd ÷ range organizing effect of bcd ÷ activity on the an- activity (Frohnh0fer, 1987). In addition to the anterior teroposterior pattern (Frohnh0fer et al., 1987). The amount defects, stau, as a member of the posterior-group genes, of transplantable bcd + activity required to rescue bcd- affects the development of the abdomen. mutant embryos is dependent on the number of bcd ÷ copies in the donor females, suggesting that the rescuing bcd Protein Distribution and Pattern in Mutants capacity of bcd ÷ is directly releated to the level of bcd of the Anterior Group mRNA present in the donor embryos. We have demon- Whole mount mutant embryos were immunostained using strated in the accompanying paper that the localized bcd anti-bcd polyclonal antibodies, and the immunostain in- mRNA serves as a source for a bcd protein gradient which tensity was measured along the anteroposterior axis as Cell 96 F G J HE PS 13" PS1 PS PS1 WIIWIIIII/IIIIIIIIIIWII m PS7 IIIW#IWIII III//IIWI TH m WWIIIIIIIIIIIWIIW#IIIII (PS 7 PS 7 WIIII@#II~ F/1/1////////////////////////////1///////////////k, PS7 AB PS7 II///IWII/////II///I/II//////I///III ~111111111111111111111//////1111////111//11111//, PS 13 PS 13 I/lllllllllllllllllllllllllllllllllllllllllllllll/ (PS 13 m PS13 PS13 ~IIWIIIIIIIIIIIIIIIiWIIII~ TE Figure 1. Maternal Effect Mutations Affecting the Anterior Pattern of the Drosophila Embryo Cuticular patterns (A-E) and a schematic presentation of the expression pattern of eve as determined from whole mount staining of embryos at the blastoderm stage with anti-eve antibody (F-J) to illustrate changes in the fate map of mutant embryos. Anterior is at the top in all cases. (A, F) Wild type. (B) bcdEllbcd El, a strong bcd mutant. Head and thorax are replaced by a duplicated telson (PS13"), and the anterior abdomen is defective. (G) eve expression in bcdE1/Df(3R)LIN. (C, H) exuPJlexuQR. (D, I) Weak phenotype of swaWswa TM. (E, J) stauD3/stau D3 displays anterior as well as abdominal defects. PS1, PS7, and PS13 indicate parasegments 1, 7, and 13, respectively; HE, head; TH, thorax; AB, abdomen; TE, telson. described by Driever and NQsslein-Volhard (1988). For a mann and NQsslein-Volhard, 1986). The bcd protein distri- quantitative evaluation and comparison of the bcd protein bution in osk- embryos is the same as in wild-type em- concentration, we included in each staining reaction em- bryos, as shown in Figure 5B2. bryos from females with the normal diploid gene dosage In embryos at the syncytial blastoderm stage derived for bcd. To be able to distinguish these control embryos from both exu and swa females, bcd protein is distributed from the experimental embryos, the control embryos were in a very shallow gradient at 40% to 100% egg length mutant for oskar (osk) and thus lacked the pole cells (Leh- (Figures 2A, 2B, and 3A). Levels of bcd protein in swa mu- Position Determination by bcd 97 A exu A i ",.a 100 ',p ".~. q. "q.. 50 'q "'... o D ~..,. o.....~...[q o ~_ ...... ..o... Q .q g'.o_"_._.- ~..~ ~ ...=- -$ B swa t00 90 80 70 60 50 40 30 20 t0 == B e~ (0 v iO0 ffl c c .E 50 •.,. • • C stau 0 c ~',o..o,., o • E "o (3 e~ t00 90 80 70 80 50 40 30 20 t0 (gC C '°° l D BicD 50 .D. ,. o " " '~--- ......... D t00 90 80 70 60 50 40 30 20 t0 0 position ( % egglength ) Figure 3. Anti-bcd Immunostain Intensities in Mutant Embryos Quantification of immunostain intensity was as described in Driever Figure 2. bcd Protein Distribution in Whole Mounts of Mutant Em- and N0sslein-Volhard (1988). Maternal genotypes are exuPJlexu oR (A), bryos stauO31Df(2R)PC4 (B), and torWK/tor HH (C) (closed squares, heavy The maternal genotypes are exueJ/exu OR (A), swa14/swa 14 (B), lines).
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