Outside Influences


You are here

The whole is more than the sum of its parts

– Aristotle, Metaphysics

Zelzer and his team investigate joint development


The body is a sort of self-contained society, governed by the coordinated efforts of its individual organs and components. But what about the individual organs themselves? Are they “self-governing” – able to develop independently of the whole – or do they rely on outside influences to develop and function? In other words, do different growing tissues interact, helping to sculpt one another as they take shape?
In two recently published papers, Dr. Elazar Zelzer and his colleagues in the Weizmann Institute’s Molecular Genetics Department present mounting evidence that tissue interactions are a fairly influential factor in the shaping of organs.
In the formation of joints, for example, the different tissues develop from a pool of uncommitted cells called progenitor cells which, as they “grow up,” turn into the various cell types that constitute the mature joint. So, for instance, the fate of some cells in the “joint pool” is to grow into tough cartilage, while others become soft synovium (joint capsule) tissue. Keeping progenitor cells committed to their designated fate is a prerequisite for correct organ development; how they are kept on course is a key question. The answer, Zelzer believes, lies in outside influences.
One hint comes from the kicks and prods that expectant mothers experience during pregnancy: It’s long been recognized that their babies are not merely practicing to become the next Bruce Lee; but in fact, such movements play a fundamental role in normal development. When fetal movement is restricted, as in fetal akinesia deformation sequence (FADS), the result is various disorders, among them arthrogryposis multiplex congenita (AMC), which is characterized by multiple joint abnormalities. However, the exact relationship between muscular movement and joint formation remained unknown.
To shed light on the matter, former postdoctoral fellow Dr. Joy Kahan, who initiated the study, and M.Sc. student Yulia Schwartz started working backwards to try to identify the developmental checkpoint at which joint malfunctions first occur. They took four mutant strains of mice – three that don’t form any muscle in the limbs whatsoever and one that forms muscle, but is paralyzed. They genetically labeled the various progenitor cells so they could trace the events.
The team found, as they reported in Developmental Cell, that in all four scenarios, the ability to form functional joints was lost. Why should missing or paralyzed muscle affect joint development? Upon further analysis, they discovered that in the absence of muscle contractions, the joint progenitor cells’ critical “puberty” stage is disrupted: Instead of maturing into the joint-forming cells they were destined to become, these cells experience a sort of “identity crisis” and grow up to be cartilage cells
“Through our findings that muscular contraction ultimately regulates joint cell fate and formation, we have provided, for the first time, in vivo evidence highlighting the important connection between embryonic movement and organ development, showing that it’s not solely dependent on intrinsic factors,” says Zelzer.
Another example of tissue interaction can be seen in the developing vascular system. Since blood vessels supply all the other organs with all their oxygen and nutrient needs, it’s vital that their development be synchronized. The question is, does the developing organ regulate blood vessel growth or vice versa? Or are they all innately programmed to develop independently? Zelzer’s Ph.D. student Idit Eshkar-Oren turned to the skeletal system to try to provide some answers.
During the initial stages of embryonic development, the limbs are populated with blood vessels throughout. As development proceeds, the skeleton secretes anti-growth factors, causing the blood vessels to regress and making way for the growth of cartilage, which is, in turn, later replaced by bone. It would make sense, then, to find fewer new blood vessels near the skeleton and more farther away, where the anti-growth signals are weaker. Yet, this is not the case: Flanking the bony growth are areas rich in blood vessels. What regulates this unlikely patterning? Surprisingly, both processes – vessel growth and vessel regression – are governed by the skeleton. In research published in Development, the team showed that not only does the skeleton secrete negative growth factors, but it also secretes a well-known factor (VEGF) that encourages blood vessel growth. In this way, the scientists believe, the skeleton compensates for the blood vessel retreat, ensuring a sufficient supply of nutrients and oxygen nearby, even as the bones themselves are disconnected from the blood system.
Zelzer: “The evidence we have accrued from our studies clearly suggests that tissue interactions are an important factor governing embryonic organ development. Because the skeletal system is a central organ system associated with a large variety of congenital diseases and malformations, shedding more light on its embryonic development may hopefully improve our ability to treat and prevent such conditions.”
Dr. Elazar Zelzer’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; the Kirk Center for Childhood Cancer and Immunological Disorders; the David and Fela Shapell Family Center for Genetic Disorders Research; and the estate of Rubin Feryszka. Dr. Zelzer is the incumbent of the Martha S. Sagon Career Development Chair.
Mouse embryo skeleton showing sites of initial bone formation (stained red) and cartilage (green and blue), which will later be replaced by bone