XML Feed for RxPG News   Add RxPG News Headlines to My Yahoo!   Javascript Syndication for RxPG News

Research Health World General
 
  Home
 
 Latest Research
 Cancer
 Psychiatry
 Genetics
 Surgery
 Aging
 Ophthalmology
 Gynaecology
 Neurosciences
 Pharmacology
 Cardiology
 Obstetrics
 Infectious Diseases
 Respiratory Medicine
 Pathology
 Endocrinology
 Immunology
 Nephrology
 Gastroenterology
 Biotechnology
 Radiology
 Dermatology
 Microbiology
 Haematology
 Dental
 ENT
 Environment
 Embryology
  Stem Cell Research
 Orthopedics
 Metabolism
 Anaethesia
 Paediatrics
 Public Health
 Urology
 Musculoskeletal
 Clinical Trials
 Physiology
 Biochemistry
 Cytology
 Traumatology
 Rheumatology
 
 Medical News
 Health
 Opinion
 Healthcare
 Professionals
 Launch
 Awards & Prizes
 
 Careers
 Medical
 Nursing
 Dental
 
 Special Topics
 Euthanasia
 Ethics
 Evolution
 Odd Medical News
 Feature
 
 World News
 Tsunami
 Epidemics
 Climate
 Business
Search

Last Updated: Sep 19th, 2006 - 15:08:16

Nature Genetics

Embryology Channel
subscribe to Embryology newsletter

Latest Research : Embryology

   DISCUSS   |   EMAIL   |   PRINT
Faults in housekeeping genes regulating protein trafficking results in skeletal deformities
Sep 19, 2006, 15:01, Reviewed by: Dr. Priya Saxena

"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."

 
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."
 

- The study appears in the Sept. 17 online issue of Nature Genetics.
 

http://www.mc.vanderbilt.edu/reporter

 
Subscribe to Embryology Newsletter
E-mail Address:

 

Other authors on the paper include: Michael Lang, Ph.D., Lynne Lapierre, Ph.D., and James Goldenring, M.D., of Vanderbilt, and Michael Frotscher, Ph.D., of the University of Freiburg, Germany. Marshall Summar, M.D., and Todd R. Graham, Ph.D., also contributed highly valuable discussions to this research. The research was supported by the zebrafish initiative of Vanderbilt University Academic Venture Capital Fund.

Related Embryology News

Faults in housekeeping genes regulating protein trafficking results in skeletal deformities
Neural stem cells derived from human embryonic stem cells carry abnormal gene expression
Neurons grown from embryonic stem cells restore function in paralyzed rats
New stem-cell findings can help the body to cure itself
Putting avian transgenics on a par with transgenic mice
Harvard to Create Human Embryonic Stem Cell Lines
Stem Cell Study for Patients with Heart Attack Damage Seeks to Regenerate Heart Muscle
Stem cells - An alternative to skin grafting?
Bone morphogenetic protein 6 (BMP-6) factor stimulates cartilage growth from stem cells
Doctors grow organ from patients' own cells


For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

Top of Page

 

© Copyright 2004 onwards by RxPG Medical Solutions Private Limited
Contact Us