Jacob’s role in brain signalling

Jacob’s role in brain signalling

Jacob’s role in brain signalling

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Conditional KO in 20 weeks
Latest publications
Frank’s blog
Timeline update

Brain mouseJacob’s role in brain signalling

The brain has an incredible ability to reorganise itself by creating new neural pathways. This neuroplasticity is essential for healthy development, learning, and memory. While neuroplastic change is often triggered by injury, disease, or environmental stimuli, there are many genetic conditions that also affect how the brain develops and repairs itself.

Dr. Michael Kreutz and Dr. Christina Spilker are researchers at the Neuroplasticity (NPlast) research group at the Leibniz Institute for Neurobiology in Magdeburg, Germany. The group focuses on researching molecular mechanisms of neuronal and synaptic plasticity. This refers to the ability of neurons to respond to brain and network activity with long-lasting structural changes and by strengthening of the corresponding synapses. The NPlast group is specifically interested in molecular dynamics of the postsynaptic density and mechanisms of protein transport from synapse to nucleus. They investigate how these proteins regulate gene expression and how it feeds back to synaptic function.

In their recent publication, a research team led by Dr. Kreutz investigated the role of Jacob protein, encoded by the Nsmf gene, using an Nsmf knockout mouse model generated by Ozgene. Their specific interest was the link between Jacob/Nsmf and Kallmann syndrome (KS). KS is a rare neurodevelopmental disorder that causes delayed, reduced, or absent puberty and consequently infertility. KS is also associated with anosmia (loss of the sense of smell) or hyposmia (reduced ability to smell).

Mutations in NSMF (NMDA receptor synaptonuclear signalling and neuronal migration factor) have been associated with KS. The Kreutz group has previously demonstrated that Jacob is involved in NMDA receptor synaptonuclear signalling. In their latest paper, Dr Spilker and colleagues found that mice that are deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, they exhibit hippocampal dysplasia, reduced plasticity at CA1 synapses and deficits in hippocampus dependent learning.

The nuclear translocation of Jacob is induced in early development by brain-derived neurotrophic factor (BDNF) in an NMDAR-dependent manner, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. The Nsmf knockout mice also showed reduced hippocampal Bdnf mRNA and protein levels, as well as reduced pCREB levels during dendritogenesis. Furthermore, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons lacking Jacob.

The data shown by Dr. Spilker and her colleagues suggests that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signalling, subsequent nuclear import of Jacob, activation of CREB, and enhanced Bdnf gene transcription. Ultimately these factors lead to hippocampal dysplasia.

For more information regarding Dr. Spilker and Dr. Kreutz’s research, please see the recent publication below.

For more information on Ozgene mouse models, please see Ozgene services.

20 weeksConditional KO in 20 weeks

We have now completed a conditional KO project in only 20 weeks, breaking the previous record of 24 weeks. The mouse line was generated on C57BL/6 background, utilising goGermline and gene targeting via homologous recombination. Give our new, faster timelines a go and contact us to discuss your project.

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Latest publications

FEATURED – PLoS Genet. 2016 Mar 15.
A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.
Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A, Lopez-Rojas J, Montag D, Angenstein F, Bär J, D’Hanis W, Roskoden T, Mikhaylova M, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR. – Leibniz Institute for Neurobiology; Otto-von-Guericke University; Functional Neuroimaging Group, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE); University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Germany.   [read]

Nat Commun. 2016 May 4.
TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.
Aizawa S, Okamoto T, Sugiyama Y, Kouwaki T, Ito A, Suzuki T, Ono C, Fukuhara T, Yamamoto M, Okochi M, Hiraga N, Imamura M, Chayama K, Suzuki R, Shoji I, Moriishi K, Moriya K, Koike K, Matsuura Y. – Osaka University; Hiroshima University School of Medicine; National Institute of Infectious Diseases, Tokyo; Kobe University Graduate School of Medicine; University of Yamanashi; The University of Tokyo, Japan.   [read]

J Neurosci. 2016 May 25.
Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex.
Huang Z, Sun D, Hu JX, Tang FL, Lee DH, Wang Y, Hu G, Zhu XJ, Zhou J, Mei L, Xiong WC. – Charlie Norwood Veterans Administration Medical Center; Medical College of Georgia, Augusta University, Georgia. Wenzhou Medical University, Wenzhou, Zhejiang; Northeast Normal University, Changchun; Xuzhou Medical College; Zhejiang Provincial People’s Hospital, Hangzhou; Northeast Normal University, Changchun, China.   [read]

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Frank’s blog: Leaning (on) our healthcare system

I usually do not reblog or comment on other people’s articles, however, the blog by Dr. Patricia Gabow and Ken Snyder in response to “Medical Taylorism” struck a chord with me. I have recently spent a lot of time in hospitals and witnessed disrespect for processes and people, staff as well as patients. Lean is all about respect for every individual, and listening to the voice of the customer, i.e. the patient’s journey…

Go to blog

technical timeline

Technical timeline

When all processes produce the desired result first time, the timeline can be as short as 18 weeks.

fastest project

Fastest project

Our fastest conditional KO project took 20 weeks from vector construction to germline transmission.

current average

Current average

The Simple Moving Average timeline of our recently completed conditional KO projects is 31 weeks.