Hox genes code for transcription factors that play an essential role in the regionalization of the anterior-posterior axis in animals. Thus, they function by providing specific identities to the different segments of the body plan, which translates in the differentiation of the correct structures in each segment. Well-known and astonishing examples of homeotic transformations include those that transform Drosophila antennas into legs or flies with two pairs of wings. Hox genes have been highly conserved through evolution and, for example, Hox genes from flies can replace the function of their vertebrate orthologs.
The function of Hox genes has been (and still is) largely studied during the embryonic development of a large number of invertebrate and vertebrate species. During regeneration, specially in those cases in which large structures or body regions need to be re-grown, it is easy to imagine that Hox genes should have an important function in the re-establishment of the positional identity within the regenerate. However, and in contrast to the observations that conserved signalling pathways such us the BMP, Wnt/beta-catenin, Hedgehog and FGFs play important functions during regeneration, many less functional studies have been reported on the role of Hox genes during regeneration. Thus, whereas several families of genes containing an homeobox domain (pbx, prox, pitx, six, Rx, msx,…) have been functionally characterized during regeneration in planarians, tunicates or amphibians, most of the studies on Hox genes and regeneration focus on their changes in expression during this process. Some of those studies were important for example to show how Hoxc10L is not expressed during axolotl forelimb development but it is upregulated during regeneration, pointing to a “regeneration-specific” expression of this gene (http://www.ncbi.nlm.nih.gov/pubmed/11150241). Also, few years ago it was reported that Hoxc13 orthologs are important for zebrafish tail regeneration where are required for blastema cells proliferation and growth (http://www.ncbi.nlm.nih.gov/pubmed/17437127).
Now, a recent paper from the laboratory of Elena Nokikova and Milana Kulakova reports on the expression of 10 Hox genes during regeneration in the polychaete Alitta (Nereis) virens (http://www.ncbi.nlm.nih.gov/pubmed/23638687). During postlarval development the Hox genes are mainly expressed in a posterior-to-anterior gradient mode. These annelids can regenerate their posterior body end. After amputation the terminal pygidial structures and prepygidial growth zone (GZ) form first and then the new segments appear sequentially. The authors divided the Hox genes into four groups depending on their changes in expression during regeneration. Three genes (early genes: Nvi-Lox5, Nvi-Lox2 and Nvi-Post2) were rapidly upregulated in the nervous system near to the amputation plane by 4 hpa (hours post amputation). Then, Nvi-Hox5 and Nvi-Hox7 (middle genes) expression patterns in the nervous system were reorganized by 10 and 18 hpa, respectively, before active proliferation in the GZ started. Next, two Hox genes, Nvi-Hox2 and Nvi-Hox3 (middle genes), that are not expressed in a graded manner but specifically found in the GZ were upregulated de novo by 10 hpa. Nvi-Hox2 first appeared in two bilateral domains at the amputation plane. By 2 dpa (days post amputation) this gene was expressed in the mesoderm and ectoderm of the area between the forming pygidium and the last body segment. By 7 dpa it was detected in the mesoderm of the GZ and the mesoderm and ectoderm of the newly formed segments. Nivi-Hox3 was also first seen by 10 hpa and as regeneration proceeds got restricted to the ectoderm of the GZ. Finally, there are three genes (late genes: Nvi-Hox1, Nvi-Hox4 and Nvi-Lox4) whose expression patterns changed at late stages of regeneration once proliferation and organogenesis were under their way.
Based on all these expression patterns and dynamics the authors divided the regeneration process in two phases: during the first 48 hpa the expression patterns were reorganized inside the new body boundaries. The second phase (that overlaps with the first one) started around 24 hpa when the blastema was formed. Most of the Hox genes were highly expressed within the blastema and the rudiment of the terminal structures that were evident by 3 dpa.
Because during postlarval development Hox genes are expressed in a anterior-to-posterior gradient in segments that are morphologically similar, the authors suggest that Hox genes at this stage provide the positional information needed to determine the position of body parts. Thus, after amputation the expression of most of the Hox genes of the early and middle groups is reorganized so the last body segments adjacent to the amputation plane acquire the Hox pattern typical of the posterior body end. Remarkably the blastema seems to be formed after the Hox genes have been reorganized to the new body proportions.
Future functional experiments should help to determine the exact role of the Hox genes during not only the re-patterning of the body during polychaete regeneration but also in other models such as planarians or amphibians.