Coupling of cell migration with neurogenesis by proneural bHLH factors

Abstract

After cell birth, almost all neurons in the mammalian central nervous system migrate. It is unclear whether and how cell migration is coupled with neurogenesis. Here we report that proneural basic helix-loop-helix (bHLH) transcription factors not only initiate neuronal differentiation but also potentiate cell migration. Mechanistically, proneural bHLH factors regulate the expression of genes critically involved in migration, including down-regulation of RhoA small GTPase and up-regulation of doublecortin and p35, which, in turn, modulate the actin and microtubule cytoskeleton assembly and enable newly generated neurons to migrate. In addition, we report that several DNA-binding-deficient proneural genes that fail to initiate neuronal differentiation still activate migration, whereas a different mutation of a proneural gene that causes a failure in initiating cell migration still leads to robust neuronal differentiation. Collectively, these data suggest that transcription programs for neurogenesis and migration are regulated by bHLH factors through partially distinct mechanisms.cortical migration ͉ doublecortin ͉ neuroD ͉ neurogenin ͉ RhoA

Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development

“…Although we show that endocrine differentiation and delamination are two concurrent processes during normal pancreas development, they are independent. In the developing cortex, Ngn2 has also been shown to control migration independently of differentiation, as the two programs can be uncoupled (Hand et al, 2005;Ge et al, 2006). Some targets that are activated are transcriptionally controlled by Ngn2 binding to E-boxes in their promoter (Ge et al, 2006).…”

“…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).…”

“…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). In this tissue, although the binding of Ngn2 to DNA is required for inducing differentiation it is not necessary for migration (Hand et al, 2005;Ge et al, 2006). The migration program is activated as the RhoA GTPase, a regulator of actin dynamics, is repressed.…”

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.…”

“…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.…”