New role revealed for neurogenesis protein associated with schizophrenia.


Proneural proteins of the class I/II basic-helix-loop-helix (bHLH) family are transcription factors that are highly conserved from invertebrates to humans. Class I bHLH proteins are expressed in a broad number of tissues during development, while class II bHLH protein expression is more tissue restricted.  The current understanding of the function of class I/II bHLH transcription factors in both invertebrate and vertebrate neurobiology is largely focused on their function as master regulators of embryonic neurogenesis. Now, a study from researchers at Drexel University shows that Transcription Factor 4  (TCF4), a human class I bHLH protein, remains present in cells after neurogenesis where they turn jobless cells into neurons.  The team state that their discovery that a particular protein give cells a job and also sticks around to tell them how to do these new assignments could provide insight into schizophrenia.  The opensource study is published in the journal Cell Reports.

Previous studies show that mutations in TCF4 have been reliably identified in genome-wide association studies as a susceptibility risk factor for schizophrenia. However, it is unknown whether this disease is due to defects in neurogenesis, in mature differentiated cells, or both. Literature suggests that disrupted neurogenesis and/or neural differentiation may be partly responsible. For example, TCF4 is expressed widely in the nervous system during mouse embryonic development and is also expressed in germinal layers of the postnatal mouse brain.  Therefore, it has been suggested that schizophrenia and other neurocognitive disorders may also be a result of dysfunction in postmitotic/differentiated neurons. The current study analyzes the effect of altering TCF4 using a mouse model to further understand the contributions of type I bHLH proteins in postmitotic neurons after neurodevelopment.

The current study shows in a mouse model that TCF4 is present in mouse brain postmitotic neurons, and that mouse TCF4 also functions to restrict neurite branching/synaptogenesis.  Results show that not only do the proteins take a cell that doesn’t have a job and give it one, it also tells that cell how to do it.  Data findings show that TCF4 also regulates the number of synapses in neurons, it had not disappeared and was still present and very active.

The lab state that these findings are particularly important because of the association TCF4 gene variants have with schizophrenia and Pitt-Hopkins Syndrome, a neurodevelopmental disorder.  They go on to add that as mutations in TCF4 are associated with both diseases they hypothesize that TCF4 is most likely involved in helping to form the proper number of synapses a cell makes, so that the information flow in the nervous system doesn’t get confused and dysfunctional. The researchers conclude that when a patient loses these proteins, they suddenly get too many synapses which disrupts the nervous system function.

The team surmise that their findings suggest that depending on the severity of the mutation’s effect on TCF4, there may be differing outcomes.  They go on to add that too severe a mutation may cause a strong effect like Pitt-Hopkins Syndrome, while other changes in the gene may increase the risk of schizophrenia.  For the future, the researchers state that further study of the presence of TCF4 in neurons could uncover more about the relationship between synapse number and adult nervous system function, as well as autism.

Source: Drexel University

 

Da Is Present in Postmitotic Neurons of the VNC.  Confocal images of third instar VNC labeled with α-Da (red), DAPI (blue), and membrane bound GFP (green). The membrane bound GFP expressed by elav-GAL4 labels postmitotic neurons.  (A–C) WT VNC. (A) VNC labelled for Da, ELAV, and DAPI (DNA). (B) ELAV channel alone from (A). (C) Da channel alone from (A). Arrows mark postmitotic neuron highlighted in inset.  (D–F) VNC where Da expression is knocked down. (D) VNC labelled for Da, ELAV, and DAPI (DNA). (E) ELAV channel alone from (D). (F) Da channel alone from (D). The arrows mark the postmitotic neuron that is highlighted in the inset.  Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons.  Marenda et al 2016.

Da Is Present in Postmitotic Neurons of the VNC. Confocal images of third instar VNC labeled with α-Da (red), DAPI (blue), and membrane bound GFP (green). The membrane bound GFP expressed by elav-GAL4 labels postmitotic neurons. (A–C) WT VNC. (A) VNC labelled for Da, ELAV, and DAPI (DNA). (B) ELAV channel alone from (A). (C) Da channel alone from (A). Arrows mark postmitotic neuron highlighted in inset. (D–F) VNC where Da expression is knocked down. (D) VNC labelled for Da, ELAV, and DAPI (DNA). (E) ELAV channel alone from (D). (F) Da channel alone from (D). The arrows mark the postmitotic neuron that is highlighted in the inset. Type I bHLH Proteins Daughterless and Tcf4 Restrict Neurite Branching and Synapse Formation by Repressing Neurexin in Postmitotic Neurons. Marenda et al 2016.

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