Caudal Protein

Caudal protein (Cad) was identified originally as a homeodomain protein in Drosophila, but homologues have subsequently been found in vertebrates as well. It belongs to the superfamily of DNA-binding homeodomain transcription factors. Caudal messenger RNA, which is supplied by the mother in the unfertilized egg; is required for proper segmentation of posterior segments in insects and for the development of the posterior lineage in vertebrates. In Drosophila, Caudal has been shown to bind to promoter elements and to activate directly the transcription of several segmentation genes. In this process, it cooperates with other transcriptional activators of segmentation genes, eg, Bicoid (another homeodomain protein). At the preblastoderm stage, Caudal protein forms a gradient, which is generated by translational repression caused by Bicoid binding to the cad mRNA. Although this early function appears to be specific to Drosophila (and other long-germ-band insects), the zygotic function of Caudal, specification of the most posterior segments in insects or posterior cell lineage in vertebrates, appears to be conserved throughout the animal kingdom.

 The caudal (cad) gene of Drosophila was first isolated as a homeobox-containing gene by cross-hybridization to the homeobox of Ultrabithorax (Ubx) and others (1, 2). The cad homeodomain shares 58% identity with that of ftz, and 53% and 52%, respectively, with those of Antp and Ubx. During Drosophila development, cad is expressed both maternally and zygotically. The maternal expression is detected in the germ line in nurse cells during oogenesis, and its mRNA accumulates in the developing oocyte. At the end of oogenesis, the cad mRNA is distributed evenly throughout the oocyte. No Cad protein is detected during oogenesis. Cad protein is first detected beginning with nuclear division cycles 6 or 7, just prior to the formation of the syncitial blastoderm. From this stage on to the 13 nuclear cycle, the distribution of Cad protein forms a concentration gradient throughout the embryo and along the anterior-posterior axis, with its maximum at the posterior end. The cad mRNA remains uniformly distributed throughout the cytoplasm to the 12 nuclear cleavage; subsequently, it follows the protein gradient, when it is then distributed as a concentration gradient itself. Nevertheless, the protein gradient precedes the mRNA gradient by several nuclear cycles, so that the mRNA gradient is not relevant for the generation of its protein gradient. Following the final nuclear cleavage during cellularization of the blastoderm, the maternally-derived cad mRNA disappears, and with it the protein translated from it (1-3).

Formation of the protein gradient from the initially uniformly distributed mRNA is generated by translational repression in the anterior regions of the embryo. Another maternally provided homeodomain protein, Bicoid, binds the cad mRNA and prevents its translation (4, 5). This is the only reported example of a homeodomain protein controlling the expression of another homeodomain factor at the level of its mRNA by translational repression. Caudal protein also accumulates in the pole cells during their formation and is present there for several hours of embryogenesis. There is no de novo expression in the pole cells, however, and all the protein present was synthesized from the maternally provided mRNA. Formation of the Caudal protein gradient does not depend on zygotic gene expression. In older unfertilized eggs, an anterior-posterior gradient is detected that is similar to that normally present in embryos of the same stage (2, 3). Maternally expressed Caudal has also been reported in other insects, such as Bombyx mori (6).

Zygotic expression of Caudal protein in Drosophila begins during cellularization of the blastoderm as a stripe in the posterior region of the embryo corresponding to the anlagen of the most posterior segments (the presumptive abdominal segments A9/A10, parts of the telson) and the hindgut. At the extended-germ-band stage, and throughout the rest of embryogenesis, cad is expressed in posterior midgut cells, the Malpighian tubules, the anal plate and, at weaker levels, during germ-band extension in pair-rule-like stripes (1-3). In third instar larvae, cad is expressed in the Malpighian tubules, the posterior midgut, the gonads of both sexes, and in the anlagen of the anal plates and the hindgut, within the genital (3). Most aspects of the zygotic expression are conserved in those vertebrates that have been analyzed (7-10).

In Drosophila, the function of the Caudal transcription factor is required for segment specification in the thoracic and abdominal regions by regulating the transcription of several segmentation genes (11-14). Embryos lacking both maternal and zygotic Cad protein are severely shortened, with variable deletions of many of the thoracic and abdominal segments. Zygotically provided protein can, however, largely rescue these defects. Ectopic expression of Caudal protein throughout the embryo at the blastoderm stage leads to phenotypes that are somewhat opposite to the phenotypes observed in cad-defective embryos (15). Analysis of the cis-acting elements of several segmentation genes has demonstrated that Cad is directly activating transcription of fushi tarazu (11) and other segmentation genes (12-14). Caudal acts in concert with Bicoid, and is partially redundant, in controlling the expression of the downstream targets, the segmentation genes (12, 13).

Embryos from wild-type mothers that lack zygotic function display an absence of parts of the most posterior segments, the terminalia; in particular, the anal tuft, parts of the anal pads, and the terminal sense organs, all structures that are derived from a cryptic tenth abdominal segment, are deleted (2). The isolation and developmental expression analysis of Caudal homologues in vertebrates (7-10) has suggested that this aspect of Caudal function, specification of most posterior segments or posterior lineage in vertebrates, has been conserved throughout evolution. Based on the expression patterns of some of the vertebrate Caudal homologues, additional roles for this subfamily of homeodomain transcription factors have been proposed; eg, participation in rostrocaudal axial patterning or in the development and regeneration of the liver (16, 17). However, all the assumptions of Caudal function (s) in vertebrate development are based purely on the respective expression patterns, and no loss-of-function mutants have been reported to date. Thus, all these proposed roles of vertebrate Caudal homologues await confirmation by the analysis of specific mutants, eg, knockout mice, or the potential identification of mutants in other model systems, such as the zebrafish.

References 

1. M. Mlodzik, A. Fjose, A. Gehring, and W. J. Gehring (1985) EMBO J. 4, 2961–2969. 

2. P. M. MacDonald and G. Struhl (1986) Nature 324, 537–545. 

3. M. Mlodzik and W. J. Gehring (1987) Cell 48, 465–478. 

4. J. Dubnau and G. Struhl (1996) Nature 379, 694–699. 

5. R. Rivera-Pomar, D. Niessing, U. Schmidt-Ott, W. J. Gehring, and H. Jäckle (1996) Nature 379, 746-749.

6. X. Xu, P. X. Xu, and Y. Suzuki (1994) Development 120, 277–285. 

7. A. Frumkin, Z. Rangini, A. Ben-Yehuda, Y. Gruenbaum, and A. Fainsod (1991) Development 112, 207-219 .

8. A. Frumkin et al. (1993) Development 118, 553–562. 

9. J. S. Joly et al. (1992) Differentiation 50, 75–87. 

10. F. Beck, T. Erler, A. Russell, and R. James (1995) Dev. Dyn. 204, 219–227. 

11. C. Dearolf, J. Topol, and C. Parker (1989) Nature 341, 3430–3433. 

12. R. Rivera-Pomar, X. Lu, N. Perrimon, H. Taubert, and H. Jäckle (1995) Nature 376, 253–256. 

13. C. Schulz and D. Tautz (1995) Development 121, 1023–1028. 

14.  T. Hader et al. (1998) Mech. Dev. 71, 177–186. 

15. M. Mlodzik, G. Gibson, and W. J. Gehring (1990) Development 109, 271–277. 

16. A. V. Morales, E. J. de la Rosa, and F. Pablo (1996) Dev. Dyn. 206, 343–353. 

17. U. Doll and J. Niessing (1996) Eur. J. Cell Biol. 70, 260–268. University Press, Oxford, U.K.   

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