The astrocyte block

Close homolog of L1 (CHL1), a glial scar component, blocks axonal regeneration and inhibits functional recovery after spinal cord injury (J. Neurosci. 27, 7222–7233).

When the spinal cord is injured, inhibitory molecules in the lesion prevent effective axon regeneration. Blocking these molecules allows axons to regrow across the lesion site and reconnect the nervous system.

Igor Jakovcevski et al. found that after spinal cord injury, CHL1 was expressed on the surface of axons, as well as on the astrocytes of the 'glial scar', a structure found at the lesion site that is a barrier for regenerating axons. CHL1-deficient mice had more robust axon regeneration and motor recovery than wild-type mice. In a coculture system, neurite extensions were shorter only when both neurons and astrocytes expressed CHL1, suggesting that homophilic CHL1 interactions between the two cell types block axon outgrowth in vitro and regeneration in vivo. – EC

The smoking gun

A transforming gene fusion leads to the onset of non–small cell lung cancer (NSCLC), according to a study in Nature (doi:10.1038/nature05945).

Mutations in the epidermal growth factor receptor gene are well-known in NSCLC, but these mutations are not often found in the tumors of smokers. In a smoker's tumor, Manabu Soda et al. detected a transcript that encoded a fusion protein of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) that was formed by a small chromosomal inversion. Dimerization of the EML4-ALK fusion protein through the EML4 basic domain activated the kinase domain of ALK, which led to cellular transformation. The EML4-ALK gene fusion was detected in 7% of NSCLC tumors tested in two cohorts, among both smokers and nonsmokers, and with two distinct inversion points. This finding holds promise for quick screening of tumors for the fusion protein transcript, and for targeting of the kinase activity. – KS

BACE hit

Stroke is considered a risk factor for Alzheimer's disease. Apoptotic pathways are induced after stroke, and now Giuseppina Tesco et al. report that caspase activity blocks the degradation of β-site amyloid precursor protein–cleaving enzyme (BACE), one of the enzymes that generate pathogenic β-amyloid (Aβ) (Neuron 54, 721–737).

Caspase activity increases Aβ levels, but the underlying mechanism was unknown. The authors found that Golgi-localized γ-ear–containing ARF binding protein 3 (GGA3) is necessary for the degradation of BACE. During apoptosis in vitro, GGA3 is cleaved by caspases, allowing BACE levels to rise.

In a rat model of stroke, Tesco et al. reported GGA3 cleavage products and BACE accumulation, showing that caspase activity regulates this pathway after injury. What's more, the investigators found low levels of GGA3 and high levels of BACE in temporal cortex samples from individuals with Alzheimer's disease, suggesting that GGA3-targeted degradation of BACE may be pathologically important. Targeting this pathway may be a way to regulate BACE activity therapeutically. – KS

Noonan's heart

Gain-of-function RAF1 mutations can lead to Noonan syndrome and hypertrophic cardiomyopathy (HCM), according to two studies in Nature Genetics (doi:10.1038/ng2073 and doi:10.1038/ng2078).

Noonan syndrome is a heterogeneous disorder that results in short stature, mental retardation and developmental defects such as facial dysmorphia and heart abnormalities. Mutations affecting the RAS pathway are linked to this syndrome, but 40% of cases are of unknown cause.

Bhaswati Pandit et al. and Abdur Razzaque et al. sequenced the genes of other components of the RAS pathway in samples from individuals with Noonan syndrome, and identified several alleles of RAF1 that encoded an activated protein. These mutations were enriched in Noonan syndrome associated with HCM, suggesting that RAF1 may have a specific role in the development of this heart condition.

One therapy for Noonan syndrome is growth hormone injections, but Razzaque et al. note that these may exacerbate HCM. Pandit et al. went on to detect a RAF1 mutation in an individual with HCM who appeared nonsyndromic, suggesting that this is the first RAS-pathway mutation responsible for a heart abnormality. – KS

Tregs take their folic acid

T regulatory cells (Tregs) are normally in an 'activated' state, making them difficult to distinguish from other activated T cells using classical surface markers. Tomoyuki Yamaguchi et al. report that Tregs constitutively express high amounts of folate receptor 4 (FR4), a subtype of the receptor for the vitamin folic acid (Immunity doi:10.1016/j.immuni.2007.04.017).

Yamaguchi et al. found that FR4 expression was high on Tregs both before and after antigen stimulation. High FR4 expression distinguished Tregs from effector and naive T cells, which maintain intermediate or low FR4 expression, respectively.

Alloantigen-stimulated FR4-expressing Tregs suppressed graft rejection, and an FR4 monoclonal antibody reduced Treg numbers and improved tumor immunity in mice. Blocking FR4 in normal mice resulted in autoimmunity, suggesting that FR4 expression is functionally important. Perhaps FR4 can be used to isolate Treg populations for the manipulation of immune responses in the clinic. – KJ

Tuberculosis on the run

Cytosolic Mycobacterium tuberculosis divides better than it does in the phagosome and also induces apoptosis of the host cell (Cell 129, 1287–1298).

Phagocytosis – just the first step? Credit: SPL / Photo Researchers, Inc

M. tuberculosis and related strains are taken up by host macrophages and dendritic cells into phagosomes, where they persist and replicate. M. tuberculosis is also found in the cytosol, but it was unclear how cytosolic bacteria differed from those in the phagosome.

In cultured dendritic cells, Nicole van der Wel et al. found that cytosolic bacteria divided faster than phagosomal bacteria, suggesting that the cytosol is a preferred replication site for M. tuberculosis. Translocation to the cytosol was only performed by live bacteria that secrete proteins associated with virulence. Seven days after infection, cells with cytosolic bacteria had a higher rate of apoptosis, which potentially serves as a method of bacterial dispersal.

Of clinical interest, the vaccine strain M. bovis BCG does not translocate to the cytosol, and consequently may induce a different immune response than M. tuberculosis does. This difference in life cycle may account for the vaccine's shortcomings against highly infectious forms of the disease. – KS

Written by Eva Chmielnicki, Kate Jeffrey and Katherine Stevens