Phosphorylation of Neurogenin2 Specifies the Migration Properties and the Dendritic Morphology of Pyramidal Neurons in the Neocortex

Abstract

The molecular mechanisms specifying the dendritic morphology of different neuronal subtypes are poorly understood. Here we demonstrate that the bHLH transcription factor Neurogenin2 (Ngn2) is both necessary and sufficient for specifying the dendritic morphology of pyramidal neurons in vivo by specifying the polarity of its leading process during the initiation of radial migration. The ability of Ngn2 to promote a polarized leading process outgrowth requires the phosphorylation of a single tyrosine residue at position 241, an event that is neither involved in Ngn2 direct transactivation properties nor its proneural function. Interestingly, the migration defect observed in the Ngn2 knockout mouse and in progenitors expressing the Ngn2(Y241F) mutation can be rescued by inhibiting the activity of the small-GTPase RhoA in cortical progenitors. Our results demonstrate that Ngn2 coordinates the acquisition of the radial migration properties and the unipolar dendritic morphology characterizing pyramidal neurons through molecular mechanisms distinct from those mediating its proneural activity.

Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development

“…Similarly, neurons differentiate upon expression of Ngn1, 2, or 3 (Sommer et al, 1996;Ma et al, 1999;Hand et al, 2005;Ge et al, 2006). In the cortex, Ngn2 also promotes the migration of neurons through long distances to reach their final position and form the typical layered organization (Hand et al, 2005;Ge et al, 2006).…”

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia

“…NEUROG2 has also been associated with other important functions modulated by interactions with transcriptional regulators 23, 30, 31, 32. Based on this, we speculated that NEUROG2 dysregulation could affect downstream genes; this hypothesis was confirmed by identification of an overexpression of RND2 in FCD type II.…”

“…RND2 is also transiently expressed in the ventricular zone; during embryonic cerebral cortex development,23 it has a role in the regulation of actin cytoskeleton organization33 and in radial migration of newborn excitatory neurons 31. Rnd2‐deficient neurons in mouse fail to transit from the multipolar to the bipolar stage,32 suggesting that the excessive levels of RND2 in FCD type II are detrimental to the organization and orientation of radially migrating neurons, which could ultimately be implicated in the complete dyslamination observed in the dysplastic tissue. Furthermore, abnormal cell migration speed could be consistent with the presence of heterotopic clusters of neurons located within the white matter (see Fig 5B),8 as well as an increase in the number of neurons found in the upper cortical layers, mainly in the molecular layer, as noticed in pediatric patients with FCD 34…”

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

“…Evidence suggests that the basic helix-loop-helix transcription factors neurogenin-2 and NeuroD affect dendritic morphological organization in cortical pyramidal neurons and granule neurons, respectively [30][31][32]. Others, such as activating transcription factor-3 (ATF-3) and signal transduction and transcription-3 (STAT3) are better characterized and induce a variety of responses in neurons during development and in response to injury and treatment.…”