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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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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.

After three years of painstaking experiments using gene-editing techniques and sensitive fate maps to label and track developing cells in fish, researchers can now describe how the small flexible bones at the ends of fins are related to fingers and toes suitable for life on land.

The work was published in the Aug. 17, 2016 issue of Nature,

"When I first saw these results you could have knocked me over with a feather," said the study's senior author, Neil Shubin, PhD, the Robert R. Bensley Distinguished Service Professor of Organismal Biology and Anatomy at the University of Chicago. Shubin is an authority on the transition from fins to limbs.

"For years scientists have thought that fin rays were completely unrelated to fingers and toes, utterly dissimilar because one kind of bone is initially formed out of cartilage and the other is formed in simple connective tissue. Our results change that whole idea.

"We now have a lot of things to rethink."

Neil Shubin PhD, the Robert R. Bensley Distinguished Service Professor of Organismal Biology and Anatomy, University of Chicago, Illinois, USA.

To unravel how fins might have transformed into wrists and fingers, researchers worked mostly with a standard fish model: zebrafish.

Tetsuya Nakamura, PhD, a postdoctoral scholar in Shubin's lab, used a gene-editing technique, CRISPR/Cas to cut and insert genes into the zebrafish. Clustered regularly interspaced short palindromic repeats (CRISPR, pronounced crisper) are pieces of single-celled organisms. These single celled organisms have all their water-soluble components (proteins, DNA and metabolites) together within the cytoplasm enclosed by one cell membrane, rather than in separate compartments. Short segments of "spacer DNA" can be cut by CAS proteins to isolate genes or gene elements.

In zebrafish to delete important genes linked to limb-building, reseraches selectively bred zebrafish with multiple targeted gene deletions. Nakamur spent more than two years building and cross breeding fish mutants, a project begun at the Marine Biological Laboratories in Woods Hole, Massachusetts. By "knocking out" genes, he reverse engineered how the fin is built, in order to map every component of the process.

At the same time, Andrew Gehrke PhD, a former graduate student in Neil Shubin's lab, refined cell-labelling techniques to map when and where specific embryonic cells migrated as the fish and mice grew and developed.

"It was one of those eureka moments," Gehrke said. "We found that the cells that mark the wrists and fingers of mice and people were exclusively in the fin rays of fish."

The team focused on Hox genes, which control the body plan of a growing embryo along the head-to-tail, or shoulder-to-fingertip, axis. Many of these genes are crucial for limb development.

Scientists studied the development of cells, beginning in some experiments soon after fertilization, and followed them as they became part of an adult fin.

Previous work has shown that when Hox genes, specifically those related to the wrists and digits of mice (HoxD and HoxA), were deleted, the mice did not develop those structures. When Nakamura deleted those same genes in zebrafish, the long fins rays were greatly reduced.

"What matters is not what happens when you knock out a single gene but when you do it in combination," Nakamura explained. "That's where the magic happens."

Researchers also used a high-energy CT scanner toview minute fin structures within the adult zebrafish. These can be invisible, even to most traditional microscopes.

Scans revealed fish lacking specific genes lost fin rays, but small cartilage bones in fins increased in number.

The authors suspect what happened in Nakamura's mutants was that cells stopped migrating from the base of the fin to the tip. This inability to migrate to the tip meant there were fewer cells to make long fin rays, leaving more cells in the base to become flexible cartilage elements.

"It really took the combination of labeling plus knockouts to convince us that this cellular relationship between fins and limbs was real."

Andrew Gehrke PhD, Neil Shubin laboratory.

Future research includes new expeditions to find more fossil fish — such as Tiktaalik, discovered by Shubin and colleagues in 2006 — to link primitive fish development into the first four-legged animals. They are now planning experiments with Hox genes to learn the extent to which common cells form different structures in fish and people.

Understanding the evolutionary transformation of fish fins into tetrapod limbs is a fundamental problem in biology1. The search for antecedents of tetrapod digits in fish has remained controversial because the distal skeletons of limbs and fins differ structurally, developmentally, and histologically2, 3. Moreover, comparisons of fins with limbs have been limited by a relative paucity of data on the cellular and molecular processes underlying the development of the fin skeleton. Here, we provide a functional analysis, using CRISPR/Cas9 and fate mapping, of 5′ hox genes and enhancers in zebrafish that are indispensable for the development of the wrists and digits of tetrapods4, 5. We show that cells marked by the activity of an autopodial hoxa13 enhancer exclusively form elements of the fin fold, including the osteoblasts of the dermal rays. In hox13 knockout fish, we find that a marked reduction and loss of fin rays is associated with an increased number of endochondral distal radials. These discoveries reveal a cellular and genetic connection between the fin rays of fish and the digits of tetrapods and suggest that digits originated via the transition of distal cellular fates.

The research was funded by the Japan Society for the Promotion of Science Postdoctoral Research Fellowship, the Uehara Memorial Foundation Research Fellowship, the Marine Biological Laboratory, the National Institutes of Health, the National Science Foundation, the Brinson Foundation and the University of Chicago. Additional authors include Justin Lemberg and Julie Szymaszek.
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Aug 22, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Markers of the wrists and digits in the limb of a mouse (LEFT) are present in fish
and demarcate the fin rays (RIGHT). The wrist and digits of tetrapods
are the cellular and genetic equivalents of the fin rays of fish.
Image Credit: Marie Kmita and Andrew Gehrke



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