Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cellular traffic backups implicated in skeletal malformations

20.09.2006
A defective link in the intracellular protein "transit system" may lie at the heart of some craniofacial defects, new research in zebrafish suggests.

In the Sept. 17 online issue of Nature Genetics, Vanderbilt University Medical Center researchers report the identification of a mutation that causes severe skeletal deformities in zebrafish by shutting down a critical protein transport pathway.

The findings are surprising, said Ela Knapik, M.D., lead investigator on the study, because this pathway is thought to be so universal that a defect would prove fatal just hours after fertilization. But the mutant fish, named crusher, hatched and survived to nine days, albeit with striking skeletal abnormalities – craniofacial defects, kinked fins and shortened body.

The pathway affected by the crusher mutation is key to transporting proteins outside of the cell. All proteins are made in the endoplasmic reticulum (ER), a labyrinthine compartment just outside the cell's nucleus. Proteins are then "packaged" into transport containers called vesicles, which traverse the gelatinous cytoplasm of the cell's interior. The vesicles eventually dock with the Golgi, a structure that resembles a pancake stack and is the last major "transit station" of the cell. In the Golgi, proteins are modified into their active, final form before being shipped out to the surface of the cell in another type of vesicle. Once they reach their destination, the proteins either empty out into the extracellular space or take up residence in the cell membrane.

"Protein transport and secretion is a fundamental function of every living cell, in every organism," said Knapik, associate professor of Medicine and Cell and Developmental Biology. Similar mutations in yeast and cultured cells were lethal from the start, suggesting that no multicellular animal would be able to survive such a defect.

But, the crusher mutation appears to only affect chondrocytes, the cells that form the fish's cartilaginous skeleton. Chondrocytes secrete proteins like collagen into the extracellular space, laying down a rigid matrix (the extracellular matrix or ECM) that will form cartilage.

Under a microscope, type II collagen can mainly be found in the extracellular space. Only small amounts can be seen in the cytoplasm.

In the crusher fish, Knapik and colleagues found no extracellular type II collagen in the mutant tissue. Instead, the protein was either stuck within a bloated ER or associated with the proteasome, the cell's garbage disposal. In addition, the Golgi appeared shrunken and abnormal. This suggested that the protein somehow missed the first leg of its journey out of the cell, getting stuck at the first transit station, the ER.

The researchers have identified the source of the defect – a gene called sec23a, which is a critical component of the vesicles that transport proteins from ER to Golgi. But since the gene is supposedly active in all cells, just why chondrocytes are the only cell type affected by the mutation remains unclear.

"The fact that it affects only chondrocytes is very strange," Knapik said.

One possibility is that the fast growth of the craniofacial skeleton, which begins forming around day three, is more sensitive to the slow-down of protein transport than other cell types. Still, the results suggest that another unidentified mechanism for protein transport may exist in the other cell types.

"We had expected mutations in proteins like collagen or accessory matrix proteins to cause craniofacial malformations. Realistically, nobody suspected that these so-called 'housekeeping genes' are responsible for that sort of phenotype."

"For me, it's fascinating that the gene we have found was the least expected."

It turns out that the zebrafish mutant has a human counterpart, making the crusher mutant the first animal model that links ER to Golgi protein transport to a human craniofacial birth defect.

In the same issue of Nature Genetics – and back-to-back with Knapik's paper – a group of researchers from the University of California at Davis report the human variant of this gene, which causes a craniofacial condition called CLSD (Cranio-Lenticulo-Sutural Dysplasia) with strikingly similar defects to the crusher fish.

Although CLSD is a rare syndrome, there are hundreds of human congenital dysmorphologies of the skeleton, some of which might involve defects in this protein trafficking pathway. Knapik's model may provide insights into these disorders.

"No craniofacial or skeletal deformities – one of the most prominent human syndromes – had ever been linked to that pathway," Knapik said. "I'm very excited that now we have an animal model to study."

Melissa Marino | EurekAlert!
Further information:
http://www.vanderbilt.edu

Further reports about: Extracellular Golgi Knapik Mutant Mutation craniofacial crusher skeletal type

More articles from Life Sciences:

nachricht Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

NASA Protects its super heroes from space weather

17.08.2017 | Physics and Astronomy

Spray-on electric rainbows: Making safer electrochromic inks

17.08.2017 | Materials Sciences

Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

17.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>