How evolution has given us 5 fingers
Have you ever wondered why our hands have exactly five fingers? Dr. Marie Kmita's team has. Her researchers at the Institut de recherches cliniques de Montréal and Université de Montréal have uncovered a part of the mystery.
In August 2016, Dr. Neil Shubin and his team in Chicago, reveal that two genes — hoxa13 and hoxd13 — are responsible for the formation of fin rays and our fingers. "This result is very exciting, as it clearly establishes a molecular link between fin rays and fingers," says Yacine Kherdjemil, doctoral student in Marie Kmita's laboratory and first author of the Kmita article which also appears this year in Nature.
Researchers have understood that the limbs of vertebrates, including human arms and legs, once originated from fish fins.
Evolution led to the appearance of limbs and in particular — fingers in vertebrates. A reflection of changes to body plan associated with habitat change.
Primarily, a transition from an aquatic environment to a land environment.
How evolution occurred is a fascinating question begun with observations made in 1521 during the voyage of Ferdinand Magellan, by the Italian scholar Antonio Pigafetta recording the voyage. Later formalized in the publications in the 1850s by Alfred Russel Wallace and Charles Darwin.
Physical transitions are not accomplished overnight. Fossil records indicate that our ancient ancestors were polydactyl — with more than five fingers — which raises another question. What mechanism did evolution favor to create just five fingers — pentadactyly — among most current mammal species?
One observation caught the Dr. Kmita's attention:
"During development, in mice and humans, the hoxa11 and hoxa13 genes are activated in separate domains of the limb bud, while in fish, hoxa11 and hoxa13 genes are activated in overlapping domains of the developing fin."
Marie Kmita PhD, Director, Genetics and Development research unit, Institut de Recherches Cliniques de Montréal's Genetics; Associate Research Professor, Department of Medicine (accreditation in molecular biology), Université de Montréal, Adjunct Professor, Department of Medicine (Division of Experimental Medicine) Department of Biology, McGill University, Canada Research Chairholder in Molecular Embryology and Genetics.
Investigating the significance of hox domains which do or do not overlap, Yacine Kherdjemil reproduced how fish regulate overlapping hoxa11 gene domains in mouse limb buds and created mice with up to seven digits per paw — a throw back to an ancient ancestral pattern within all of us.
"It suggests that this major morphological change did not occur through the acquisition of new genes but by simply modifying their expression [amount of a gene produced]," explains Dr. Kmita.
This discovery reinforces the idea that malformations in fetal development may not be strictly due to gene mutation. They may also come from mutations in regulatory sequences governing how much of a particular gene is being expressed.
A DNA regulatory sequence is simply a segment of the DNA molecule capable of increasing or decreasing production of specific genes. Regulation of gene expression is essential to all living organisms and viruses.
"At present, technical constraints do not allow for identifying this type of mutation directly in patients, hence the importance of basic research using animal models," adds Marie Kmita PhD.
The fin-to-limb transition represents one of the major vertebrate morphological innovations associated with the transition from aquatic to terrestrial life and is an attractive model for gaining insights into the mechanisms of morphological diversity between species1. One of the characteristic features of limbs is the presence of digits at their extremities. Although most tetrapods have limbs with five digits (pentadactyl limbs), palaeontological data indicate that digits emerged in lobed fins of early tetrapods, which were polydactylous2. How the transition to pentadactyl limbs occurred remains unclear. Here we show that the mutually exclusive expression of the mouse genes Hoxa11 and Hoxa13, which were previously proposed to be involved in the origin of the tetrapod limb1, 2, 3, 4, 5, 6, is required for the pentadactyl state. We further demonstrate that the exclusion of Hoxa11 from the Hoxa13 domain relies on an enhancer that drives antisense transcription at the Hoxa11 locus after activation by HOXA13 and HOXD13. Finally, we show that the enhancer that drives antisense transcription of the mouse Hoxa11 gene is absent in zebrafish, which, together with the largely overlapping expression of hoxa11 and hoxa13 genes reported in fish3, 4, 5, 6, 7, suggests that this enhancer emerged in the course of the fin-to-limb transition. On the basis of the polydactyly that we observed after expression of Hoxa11 in distal limbs, we propose that the evolution of Hoxa11 regulation contributed to the transition from polydactyl limbs in stem-group tetrapods to pentadactyl limbs in extant tetrapods.
About the study
The research project was conducted at the IRCM's Genetics and Development research unit by Yacine Kherdjemil, Rushikesh Sheth, Annie Dumouchel, Gemma de Martino and Marie Kmita. Robert L. Lalonde and Marie-Andrée Akimenko, from the University of Ottawa, Kyriel M. Pineault and Deneen M. Wellik, from the University of Michigan, as well as H. Scott Stadler, from Shriners Hospital for Children, also collaborated on the study.
About Marie Kmita
Marie Kmita obtained a PhD in cell and molecular biology from the Université de Reims in France. She is Associate IRCM Research Professor and Director of the Genetics and Development research unit. Dr. Kmita is also Associate Research Professor in the Department of Medicine (accreditation in molecular biology) at the Université de Montréal, as well as an Adjunct Professor in the Department of Medicine (Division of Experimental Medicine) at McGill University. Dr. Kmita holds the Canada Research Chair in Molecular Embryology and Genetics. For more information, visit http://www.ircm.qc.ca/kmita.
How fish fins became fingers
One of the great transformations for descendants of fish was to become creatures that walk on land, with thick, sturdy "toes" replacing their long, elegant fins. Scientists from the University of Chicago now know how the same cells which make fin rays in fish, form fingers and toes in animals.
The research was funded by the Canadian Institutes of Health Research, the Canada Research Chairs Program, the Natural Sciences and Engineering Research Council and a grant from Shriners Hospital Research. Yacine Kherdjemil also received the IRCM - Michel-Bélanger Scholarship from the IRCM Foundation and a scholarship from the molecular biology program at the Université de Montréal.
About the IRCM
Founded in 1967, the Institut de recherches cliniques de Montréal (IRCM) is a non-profit organization that conducts fundamental and clinical biomedical research in addition to training high-level young scientists. With its cutting-edge technology facilities, the institute brings together 33 research teams, which work in cancer, immunology, neuroscience, cardiovascular and metabolic diseases, systems biology and medicinal chemistry. The IRCM also operates a research clinic specialized in hypertension, cholesterol, diabetes and cystic fibrosis, as well as a research centre on rare and genetic diseases in adults. The IRCM is affiliated with the Université de Montréal and associated with McGill University. Its clinic is affiliated with the Centre hospitalier de l'Université de Montréal (CHUM). The IRCM is supported by the Ministère de l'Économie, de la Science et de l'Innovation (Quebec ministry of Economy, Science and Innovation).
About Université de Montréal
Université de Montréal and its two affiliated schools, École Polytechnique (engineering) and HEC Montréal (business), are amongst the world's top 100 universities, according to international rankings. Founded in 1878, the campus today has over 66,000 students and 2,600 professors, making Université de Montréal the second largest university in Canada. Its students are drawn to the university by its deep roots in cosmopolitan Montreal and in consideration of its tenacious dedication to its international mission. umontreal.ca/english
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Oct 7, 2016 Fetal Timeline Maternal Timeline News News Archive
Two genes, hoxa13 and hoxd13, are responsible for the formation of fish rays — and digits.
Increasing or decreasing the amount of a hox gene appears to affect the number of digits on mice.
Image Credit: Marie Kmita PhD, University of Montreal and McGill University