8 October 2009. DISC1, or disrupted-in-schizophrenia 1, is a major candidate gene for schizophrenia and other major psychiatric disorders such as bipolar disorder. Scientists are only beginning to come to grips with the properties of DISC1, and with how the gene relates to pathology. Two recent papers may help. Researchers in Japan report that DISC1 interacts with girdin, a protein that binds to the cytoskeletal protein actin. The researchers found that the DISC1-girdin interplay helps regulate development of neuronal axons in the postnatal hippocampus, a major birthplace for new neurons in the adult brain. In a second article, researchers in the U.S. report that DISC1 helps drive formation of new neurons, also in the adult hippocampus, by attenuating the activity of the protein Akt. That kinase regulates a plethora of processes in neurons, including developmental pathways. The researchers show that DISC1 suppresses Akt by sequestering a protein called KIAA1212, which is another name for none other than…girdin.
Together, the two papers highlight girdin as a major DISC1 player and add to the growing evidence that DISC1 plays a significant role in postnatal neurogenesis. Since the Akt gene has also been linked to risk for schizophrenia and other brain disorders, such as autism and bipolar disorder (see SRF related news story), the research also hints that the DISC1/Akt pathway may be pivotal to psychiatric disorders. The papers, which appeared in the September 24 Neuron, “add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions,” wrote Kevin Mitchell, Trinity College Dublin, Ireland, in a comment to SRF (see below).
Akt 1, Scene 1
Senior author Guo-li Ming and colleagues at Johns Hopkins University, Baltimore, Maryland, explored the relation between DISC1 and Akt kinase because cells lacking the former behave very similarly to those lacking PTEN, a protein that counteracts Akt. That similarity suggested that DISC1 might suppress Akt, and, in fact, first author Ju Young Kim and colleagues found that knocking down DISC1 led to increased Akt activity in mouse newborn neurons. The researchers found that DISC1 binds to KIAA1212, a protein known to promote activation of Akt in cells. After a series of experiments to test protein-protein interactions, the researchers concluded that DISC1 suppresses Akt signaling by preventing KIAA1212, i.e., girdin, from activating the kinase.
The suppression of Akt has important consequences for the development of newborn neurons in the adult brain. The researchers found that knocking down DISC1 or PTEN, or overexpressing girdin or a constitutively active form of Akt, all led to increases in the size of neuron cell bodies and an accelerated growth and increase in number of dendrites. Newborn neurons in the adult hippocampus also tended to migrate farther than usual, beyond the granule layer and into the molecular layer, when Akt suppression was relieved by knocking down DISC1 or PTEN. The results indicated that DISC1 can regulate morphogenesis and migration of new neurons in the adult hippocampus.
What are the downstream events that mediated these responses? Akt has many substrates but Kim and colleagues found that signaling via mTOR, or mammalian target of rapamycin, plays a key role. When they suppressed DISC1 expression, mTOR signaling increased, and they were also able to rescue the effects of knocking down DISC1 in cells by adding rapamycin.
Girdin, Supporting Actor
For their part, the Japanese researchers, led by Atsushi Enomoto and Masahide Takahashi at Nagoya University, focused on girdin (girders of actin filaments) because it was previously shown to bind DISC1 and another DISC1 partner, Nudel (see Camargo et al., 2007 and SRF related news story). Enomoto and colleagues found that girdin is expressed in the mouse hippocampus by postnatal day 15, predominantly in neurons rather than neural stem cells, and mostly in the dentate granule cell layer. Because the pattern and timing of girdin expression overlaps with that of DISC1, the researchers speculated that the two proteins cooperate to regulate the development and function of neurons in the dentate gyrus of the hippocampus.
Enomoto and colleagues found that girdin is essential for the development of new neurons. After about two days in culture, rat hippocampal cells begin to polarize, developing a single long outgrowth that becomes a growing axon. This process was blocked when girdin expression was silenced by short-hairpin RNAs. The researchers also found that axon extension was severely impaired in neurons isolated from girdin-negative mice. Girdin-mediated axon growth also seems to depend on DISC1. The proteins colocalize at axonal growth cones, but in the absence of DISC1, girdin levels at growth cones was significantly reduced. The authors suggest that the role of DISC1 may be to stabilize and/or anchor girdin at those growth cones.
In vivo, girdin seems essential for the proper organization of hippocampal architecture. In girdin-negative mice, the granule cell layer of the hippocampus is sparsely populated and the CA1 region of the hippocampus consists of multilayers rather than a single layer. Mossy fibers, axons that extend from the dentate granule cells, were also severely underdeveloped in girdin-negative mice. These observations are consistent with defects in neuronal migration, which is in keeping with the findings from the Ming group and also with previous work showing that DISC1 regulates the migration and integration of newborn neurons in the hippocampus (see SRF related news story). In fact, similar to findings from Ming’s group, Enomoto and colleagues went on to show that in girdin-negative mice, newborn neurons of the dentate gyrus migrated to all levels of the granule cell layer and even the molecular layer, rather than being contained to the inner third of the granule cell layer.
What role does DISC1 play in girdin-mediated cell migration? The researchers tested this using a girdin N-terminal (NT) domain, the part of the molecule that binds to DISC1. Just the NT domain competes with the full-length girdin for DISC1 in cells, and when the authors introduced the NT domain into the hippocampus of postnatal day 5 rats, it caused similar cell migration problems to those seen in girdin-negative mice. Furthermore, they could not rescue the effects of silencing girdin expression with DISC1, indicating that girdin lies downstream of DISC1 in any signaling cascade. The researchers found that girdin lies downstream of Akt as well, because a dominant active form of the kinase also failed to rescue the effects of girdin silencing.
As noted in a Neuron Preview by David Porteous and Kirsty Millar from Edinburgh University, the two studies have some areas of disagreement. While Enomoto and colleagues’ observations suggest girdin suppression mimics loss of DISC1 in adult progenitor cells, including migratory and integration problems (see SRF related news story), Kim and colleagues report that girdin overexpression mimics DISC1 suppression. Porteous and Millar suggest that “…this perhaps indicates that both the balance of DISC1 interactome expression and the resultant stoichiometry of interactors, as well as the precise developmental timing of expression, is important.” The discrepancies may also relate to the fact that girdin seems to act as both an activator of Akt and an Akt substrate.
These studies highlight, yet again, the role of DISC1 in biological pathways that control neurodevelopment (see SRF related news story and SRF related news story). In addition to DISC1, Akt, and PTEN, other proteins that interact with DISC1 and play important roles in neurodevelopment have been implicated in schizophrenia, including neuregulin (see SRF related news story) and the ErbB4 receptor (see SRF related news story). DISC1 also suppresses another kinase, GSK3β While the GSK3β inhibitor SB216763 rescues effects of DISC1 suppression on neural progenitors (see SRF related news story), Kim and colleagues found that the compound had no effect on aberrant morphology, including dendritic expansion, of new neurons lacking DISC1. “When all the evidence is taken together, we now have a tantalizing picture of how DISC1, through Akt, GSK3β, and other protein partners yet to be fully described, may regulate both neurodevelopment and neurotransmission, two core yet often opposed concepts in schizophrenia etiology,” write Porteous and Millar.
Whether any of this will help uncover new treatments for schizophrenia remains to be seen. Though rapamycin can rescue aspects of DISC1 suppression, it is also a potent immunosuppressant and might not be suitable as a chronic treatment. If the effects of rapamycin and SB216763 are positive portents of future therapeutic strategies, write Porteous and Millar, “it will nevertheless be critical to determine exactly which aspects of the DISC1 pathway phenotype must be corrected, and when, during brain development.”—Tom Fagan.
Kim JY, Duan X, Liu CY, Jang M-H, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming G-L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009 September 24; 63:761-773. Abstract
Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakomo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron. 2009 September 24; 63: 774-787. Abstract