A new study in mice by Andrea Jurisicova and colleagues at the University of Toronto, Canada, now adds the possibility that smoking before pregnancy or while breast-feeding might substantially decrease the fertility of female offspring to the long list of possible negative outcomes.

The authors found that female mice injected under the skin with polycyclic aromatic hydrocarbons (PAHs) ” environmental toxins found in cigarette smoke ” pre-pregancy or while lactating were found to have normal sized litters. However, their female offspring had markedly reduced numbers of resting and early growing follicles ”cell clusters that each contain a single egg. Further analysis indicated that the effects of PAHs on the number of follicles in female offspring were mediated through the aryl hydrocarbon receptor (Ahr), which upregulated expression of the gene Harakiri that makes a protein that causes cells to die by a process known as apoptosis. The potential importance of these findings for women of child-bearing age was demonstrated by the observation that PAHs triggered similar molecular pathways in human ovarian tissue transplanted into immunocompromised mice.

jci/

The defect is found in the structure of the neuron itself, said Pfaff, noting that the fundamental pieces, such as the receptors capable of reading cues, all seem to be present. Without the correct orientation of receptors, however, signals cannot be read accurately, resulting in growth going off course.

A precise gradient normally exists across the cone, said Pfaff, which is disrupted in the Magellan mutants. As a result, cells lose their polarity. They literally do not know the front end from the back end, according to Pfaff. This sense of polarity is a universal feature common to all growing neurons. Therefore, Phr1 is likely to play a role in most growing neurons to ensure their structure is retained at the same time they are growing larger, he said.

Pfaff and his group identified Magellan using a novel system they had developed, in which individual motor neurons and axons can be visualized fluorescently. They were able to screen more than a quarter of a million mutations, and the mutations of interest were rapidly mapped to known genes as a result of the availability of the sequenced mouse genome “ a byproduct of the effort to sequence entire genomes such as that in the human.

The Magellan mutation is located in a gene known as Phr1, which is also active in other parts of the nervous system, indicating that it most likely functions to steer other types of neurons, such as those that enervate sensory organs or connect different regions of the brain. Studies of Magellan may therefore shed light on how a variety of neurological disorders might be treated with cell replacement strategies.

salk/