NEUROD2 represses Reelin expression and controls dendrite orientation during cortical radial migration

Gizem Guzelsoy, Cansu Akkaya, Dila Atak, Cory D. Dunn, Alkan Kabakcioglu, Nurhan Ozlu, Gulayse Ince-Dunn

Preprint posted on 27 May 2019

Article now published in Scientific Reports at

NeuroD2 ON = Reelin OFF? A recent preprint gives insight into the role of the transcription factor NeuroD2 in cortical layer formation: NeuroD2 represses Reelin expression in radially migrating cortical neurons.

Selected by Theresa Pohlkamp


Reelin is a large, secreted extracellular matrix glycoprotein and best known for its function as a guidance molecule for radially migrating neurons during brain development. In the cerebral cortex migration of neural precursors born at the ventricular zone occurs in batches, resulting in a so-called inside-out pattern with the last-born neurons closest to the pial surface. Reelin is locally expressed by Cajal-Retzius cells at the pial surface (Figure, left panel) and signals to neurons to end their journey. Whereas Cajal Retzius cells die out after birth, other arising Reelin expressing neuronal subpopulations, most notably GABAergic interneurons, stellate cells of the entorhinal cortex, and mitral cells in the olfactory bulb, persist throughout adulthood. Post-migrational Reelin signaling continues to shape the brain by acting on dendritogenesis, synaptogenesis, pruning, and synaptic plasticity (reviewed in D’Arcangelo, 2014).

The migrational journey that neural precursors undergo after asymmetric cell division at the ventricular zone is precisely controlled by the combinational expression of transcription factors. Members of the basic helix-loop-helix transcription factor family, including NeuroDs, are known to participate in this process. NeuroDs play important roles in the determination and maintenance of neuronal cell fate (reviewed in Imayoshi and Kageyama, 2014). In this preprint the authors demonstrate that NeuroD2 is a transcriptional inhibitor of the Reelin gene in radially migrating cortical neurons.  This mechanism ensures that Reelin is not ectopically expressed in migrating neurons and neurons are exposed to high levels of Reelin only upon reaching the marginal zone.

In the brain, the expression of Reelin is sharply organized and several transcription factors and chromatin modulators have been described to be involved. Little is known about the dynamics, how these factors orchestrate Reelin gene expression in time and space and how this relates to neuronal fate.


Key findings that move the field forward

By ChIP-seq analysis the authors found overlapping and unique NeuroD2 binding sites in the cortical chromosome of embryos (E14.5) and newborn (P0) mice. Multiple E14.5 target genes were involved in migration; P0 target genes were associated with later developmental processes. Since neuronal expression of NeuroD2 persists throughout life, this indicates that it regulates distinct developmental functions and neuronal fates. Among the NeuroD2 targets they found multiple intronic binding sites in the Reelin gene at both ages.

When they knocked down NeuroD2, Reelin expression was increased in cultured premature primary cortical neurons and dendritic complexity decreased. The finding of NeuroD2 as a Reelin repressor was quite surprising, since NeuroD2 is more commonly described as a transcriptional activator. Besides Reelin they found other dysregulated genes; 22 were up-regulated, and 12 down-regulated. Affected genes encoded transcriptional and translational regulators, signaling proteins, and metabolic proteins. In vivo knockdown of NeuroD2 in radial migrating neurons shortened their leading-processes and caused a premature migration stop, indicating a cell-autonomous effect of ectopic Reelin. Supporting the authors’ findings, in situ hybridization by the Allen Brain Institute show an inverted expression profile for NeuroD2 and Reelin in the cortex, hippocampus, and olfactory bulb (Figure).

One of the NeuroD2 binding sites in the Reelin gene correlated with the binding of CTCF, a zinc-finger transcription factor that regulates chromatin architecture by forming loops. Recently, CTCF has been reported to govern the identity and migration of interneuron subtypes and CTCF knockout leads to an abnormal distribution of Reelin-expressing cortical interneurons (Elbert et al., 2019). Moreover, NeuroDs have been described as suppressor of the transcription factor Mash1, which facilitates GABAergic differentiation (Roybon et al., 2010). Consequently, the question arises: is the Reelin gene placed into an inactive chromatin loop, organized by transcription factors like NeuroDs and CTCF, to control radial migration and to impact the specific fate of neuronal subtypes?


Figure: In situ hybridization of Reelin (left) and NeuroD2 (right) mRNA in the developing (E15.5) mouse brain. CP = cortical plate, VZ = ventricular zone, HC = hippocampus, OB = olfactory bulb, PS = pial surface. Image credit: Allen Institute. Allen Developing Mouse Brain Atlas (2008).


My interest in this research

During my neuroscience career I worked on Reelin expression and function in the developing and adult brain. I used Reelin as a biochemical marker to characterize GABAergic interneuron subtypes. Now I study Reelin function in context of synaptic plasticity and neurodegeneration. Reelin can enhance long-term potentiation and protects the synapse against the toxic Amyloid-β peptide, which forms the Alzheimer’s disease hallmark plaques. Not much is known about why subpopulations of neurons in the adult brain express Reelin and how it contributes to brain function. Reelin binding partners and functions during neurodevelopment overlap with those during adulthood. Thus, understanding how Reelin transcription is regulated during development will also help understand regulation of Reelin expression in the adult brain. A high amount of Reelin in the adult cortex is produced by entorhinal cortex stellate cells, which are particularly prone to degeneration in Alzheimer’s disease. The stellate cells’ axons transport Reelin along the perforant pathway for secretion into the hippocampus. In the Alzheimer’s demented entorhinal cortex Reelin expression is reduced (reviewed in Stranahan and Mattson, 2010). Targeting Reelin transcription therapeutically could help maintain proper Reelin signaling to attenuate neurodegeneration and treat neuropsychiatric diseases caused by Reelin deficiency, like schizophrenia. For example NeuroD1 expression in adult-born hippocampal neurons accelerated neuronal maturation and improved memory in a mouse model of Alzheimer’s disease (Richetin et al., 2015).


Questions and future directions

In their study the authors used the whole cortex of embryonic or newborn mice for ChIP-seq. In future studies it would be interesting to see how NeuroD2 controls gene regulation in specific neuron populations of the developing, but also the mature brain. NeuroD2 ChIP-seq could be applied to neuronal subtypes derived from stem cell differentiation. Reversely, NeuroD2 overexpression or knockdown could be used to study neuronal cell fate of precursors in vitro.

How do the numerous Reelin transcription regulators that are proposed in the literature, NeuroDs, CTCF, Foxg1, Sp1, Pax6, Pbx1/2, Tbr1, MeCP2, and Ezh1, control the neuronal fate and maintenance of Reelin-expressing entorhinal cortex stellate neurons, olfactory bulb mitral cells, and cortical/hippocampal GABAergic interneurons? Does the expression of these genes change during aging or dementia?



D’Arcangelo, G. (2014). Reelin in the Years: Controlling Neuronal Migration and Maturation in the Mammalian Brain. Advances in Neuroscience 2014, Article ID 597395.

Elbert, A., Vogt, D., Watson, A., Levy, M., Jiang, Y., Brule, E., Rowland, M.E., Rubenstein, J., and Berube, N.G. (2019). CTCF Governs the Identity and Migration of MGE-Derived Cortical Interneurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 39, 177-192.

Imayoshi, I., and Kageyama, R. (2014). bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron 82, 9-23.

Richetin, K., Leclerc, C., Toni, N., Gallopin, T., Pech, S., Roybon, L., and Rampon, C. (2015). Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer’s disease. Brain: a journal of neurology 138, 440-455.

Roybon, L., Mastracci, T.L., Ribeiro, D., Sussel, L., Brundin, P., and Li, J.Y. (2010). GABAergic differentiation induced by Mash1 is compromised by the bHLH proteins Neurogenin2, NeuroD1, and NeuroD2. Cerebral cortex 20, 1234-1244.

Stranahan, A.M., and Mattson, M.P. (2010). Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer’s disease. Neural plasticity 2010, 108190.

Tags: apoer2, cortical lamination, lrp8

Posted on: 8 July 2019


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