September 28, 1999
La Jolla, CA – To make sure your heart’s in the right place, you need to add just the right amount of vitamin A.
According to new research led by scientists at The Salk Institute, the vitamin plays a critical role in helping to guide the embryonic heart to its final destination in the left side of the body of all vertebrates, including humans.
Just as important, the precise amount of vitamin A is vital. Either too much or too little of the vitamin and its derivative called retinoic acid can wreak havoc with the ultimate placement of the heart… and probably with other vital organs, including lung, stomach or liver.
“The major discovery now is that vitamin A can affect this important process in the vertebrate embryo,” said Juan Carlos Izpisúa Belmonte, an associate professor at Salk, and lead author of a study published in the current issue of the Proceedings of the National Academy of Sciences. “Either none or too much and vertebrates do not develop properly.”
Izpisúa Belmonte cautioned, however, that more work was needed before any clinical recommendations could be made about the use of vitamin A during pregnancy.
In particular, the scientists want to know more about how the vitamin influences the genetic programming of an embryo, which specific cells are impacted, and precisely how much retinoic acid is required for normal development.
“When we know these details, this will allow us to start answering the clinical questions,” Izpisúa Belmonte said.
The current study builds on recent work by Izpisúa Belmonte and others who have been seeking to understand how vertebrates organize their organs and bodies – from a single fertilized cell – along a left-right axis. The work not only would help solve a long-standing mystery, but also could provide insights into certain potentially fatal syndromes caused by severe birth defects in humans including, in some cases, the reversal of organs.
For the most part, the research has focused on the discovery of a complex cascade of genes that combine to form molecular pathways needed to help youthful cells, tissues and organs decide in which direction to take their first fateful steps – whether to go left or right. During the past year, for example, Salk scientists isolated two genes in this critical pathway.
One of these, Pitx2, is considered the final gene in the cascade before organ formation begins. The other, termed caronte, appears to be critical for transferring the early left-right information to the cells that will actually form the different organs of the body. This latter study was published in the September 16, 1999 issue of the journal Nature.
In their current studies, the Salk scientists sought to determine if vitamin A, linked to a variety of developmental disorders, played a role in left-right orientation among a variety of vertebrate animals.
Their results were surprising. Among other things, when the embryos were given large amounts of retinoic acid, the location of the heart was switched to the right side of the body.
Conversely, when the vitamin’s uptake in the embryo was blocked in the test animals, the final placement of the heart was random. That is, roughly half the hearts in the test animals were placed properly on the left side; the other half found homes on the right side.
“With an excess amount of retinoic acid, we induce the expression of Pitx2 genes on the other side and therefore the pathway is working on that side,” said Izpisúa Belmonte. “Somehow it induced the genetic cascade to put the heart in this location.
“If you block it, and there is no vitamin A, then expression of these genes doesn’t happen and then you have a randomization of the heart position. The absence of vitamin A prevents these downstream genes from being active.”
In a series of related studies, the scientists wanted to see what impact vitamin A would have on “knockout mice” missing a gene called sonic hedgehog or Shh. Without Shh, another gene called lefty1 is effectively shut down, causing the hearts of these mutated embryos to form on the opposite side.
However, when these animals were given vitamin A, their hearts grew where they should.
“This tells us that vitamin A can enter at some point in the pathway and restore normal expression of the genes such as lefty1 involved in the process,” said Izpisúa Belmonte.
The results further suggest that vitamin A is involved in a separate molecular pathway that can wipe out problems triggered directly or indirectly in the Shh pathway.
“This is something that is going to open up new avenues of investigation of how the embryo knows its left from its right,” said Izpisúa Belmonte.
Also participating in the study were Tohru Tsukui, Javier Capdevila, Koji Tamura, Concepción Rodriguez-Esteban, Sayuri Yonei-Tamura, Jorge Magallón, Bruce Blumberg and Ronald Evans, of The Salk Institute; Pilar Ruiz-Lozano, of UCSD; and Roshantha A.S. Chandrarata, of Allergan, Inc.
Funding for the study was provided by the National Institutes of Health and a grant from the G. Harold and Leila Y. Mathers Charitable Foundation.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.