Gender differences – worm version

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Depression, schizophrenia, Alzheimer’s and other neurological diseases do not treat women and men equally. For reasons not yet known, the prevalence of these diseases – and sometimes even their symptoms – varies between species. Scientists at the Weizmann Institute of Science recently compared neural networks of female and male worms, and discovered a molecular mechanism that may explain how species differ in neurological diseases in humans.

Illustration: depositphotos.com ” class=”wp-image-110702″ srcset=”https://www.hayadan.org.il/images/content3/2020/11/Depositphotos_146981463_l-2015-500×345.jpg 500w, https://www.hayadan.org.il/images/content3/2020/11/Depositphotos_146981463_l-2015-240×166.jpg 240w, https://www.hayadan.org.il/images/content3/2020/11/Depositphotos_146981463_l-2015-768×530.jpg 768w, https://www.hayadan.org.il/images/content3/2020/11/Depositphotos_146981463_l-2015-1536×1060.jpg 1536w, https://www.hayadan.org.il/images/content3/2020/11/Depositphotos_146981463_l-2015.jpg 2000w” sizes=”(max-width: 500px) 100vw, 500px”/>
Gender differences. Illustration: depositphotos.com

Depression, schizophrenia, Alzheimer’s and other neurological diseases do not treat women and men equally. For reasons not yet known, the prevalence of these diseases – and sometimes even their symptoms – varies between species. Scientists at the Weizmann Institute of Science recently compared neural networks of female and male worms, and discovered a molecular mechanism that may explain how species differ in neurological diseases in humans.

The tiny worm Caenorhabditis elegans Is an excellent model for studying neural networks in the brain, as its nervous system is relatively simple, and is the only organism so far that all neural connections in the brain have been mapped – in both sexes. When worms are born, there is no difference in the neural connections between females and males – and these only appear when they reach sexual maturity. Dr. Meital Oren-Suissa of the Department of Neurobiology and her research group hypothesized that identifying the mechanisms responsible for the appearance of these differences would help shed light on brain differences between men and women, and in particular differences related to neurological disorders.

In experiments led by the faculty scientist, Dr. Yehuda Salzberg, the scientists focused on the connection between two nerve cells that allow the worm, similar to human sensory cells, to feel its environment. Before reaching sexual maturity, this connection exists in both females and males. And preserved in males; in this context it is worth noting that although the worm female is defined as a hermaphrodite, since it produces both eggs and sperm, genetically its nervous system is female.

The worm's nervous system under a microscope.  In red: the nuclei of the nerve cells common to both sexes, in green: the nerve cells that exist only in males
The worm’s nervous system under a microscope. In red: the nuclei of the nerve cells common to both sexes, in green: the nerve cells that exist only in males

Dr. Salzberg and colleagues examined several possible mechanisms leading to the removal of connections between nerve cells and found that in adult females, a well-known molecular tag called ubiquitin is responsible for removing the particular link they investigated. In living creatures along the length and breadth of the evolutionary tree, including humans.

Scientists later revealed how the connection is removed at the molecular level. They conducted experiments on genetically engineered worms and found that the E3 enzyme, which is also found in humans and plays a key role in the ubiquitin system, marks an important receptor called DCC across the nerve cell as “destined for destruction” by the ubiquitin tag. At this point it became clear to researchers why the connection disappeared only in females. In males the breakdown of the DCC receptor is blocked by the secretion of a biochemical signal called sodium, which prevents the link between E3 and DCC. In females, on the other hand, the nerve cell does not secrete sodium, so the E3 is free to bind to the DCC and signal for destruction – and with it the entire connection. When the scientists prevented the destruction of the receptor, female worms maintained the connection between the nerve cells, and their neural circuit was the same as that of the males.

Is the DCC receptor the key to understanding gender differences in neurological diseases in humans? Many studies have shown a link between certain versions of the gene that encodes this receptor and clinical depression, schizophrenia, bipolar disorder, autism and other diseases, the common denominator of which is that their prevalence is different in men and women – and sometimes their symptoms are different. The new role of the receptor discovered in the present study points to a new research direction that may make it possible to uncover molecular mechanisms responsible for gender differences in neurological diseases. Exposing the mechanisms may in turn pave the way for the development of drugs that are specifically tailored for women or men.

The study involved research students Vladislav Pachuk, Assaf Gat, Hagar Seti and Sapir Sela from Dr. Oren-Suissa’s laboratory.

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