LMO4 functions as a co-activator of neurogenin 2 in the developing cortex

Asprer, Joanna; Lee, Bora; Wu, Chia-Shan; Vadakkan, Tegy J.; Dickinson, Mary E.; Lü, Hui; Lee, Soo Kyung

doi:10.1242/dev.061879

Cited by 35 publications

(29 citation statements)

References 68 publications

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“…Low levels of Lmo4 expression have been detected in the developing forebrain as early as embryonic day 11.5 (E11.5) (Asprer et al, 2011). We began our whole-mount expression analysis at E12.5, when Lmo4 is expressed in the neocortical preplate, and the earliest wave of postmitotic neurons is being generated (Huang et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity

et al. 2013

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The mammalian neocortex is parcellated into anatomically and functionally distinct areas. The establishment of area-specific neuronal diversity and circuit connectivity enables distinct neocortical regions to control diverse and specialized functional outputs, yet underlying molecular controls remain largely unknown. Here, we identify a central role for the transcriptional regulator Lim-only 4 (Lmo4) in establishing the diversity of neuronal subtypes within rostral mouse motor cortex, where projection neurons have particularly diverse and multi-projection connectivity compared with caudal motor cortex. In rostral motor cortex, we report that both subcerebral projection neurons (SCPN), which send projections away from the cerebrum, and callosal projection neurons (CPN), which send projections to contralateral cortex, express Lmo4, while more caudal SCPN and CPN do not. Lmo4-expressing SCPN and CPN populations are comprised of multiple hodologically distinct subtypes. SCPN in rostral layer Va project largely to brainstem, while SCPN in layer Vb project largely to spinal cord, and a subset of both rostral SCPN and CPN send second ipsilateral caudal (“backward”) projections in addition to primary projections. Without Lmo4 function, the molecular identity of neurons in rostral motor cortex is disrupted and more homogenous, rostral layer Va SCPN aberrantly project to the spinal cord, and many dual-projection SCPN and CPN fail to send a second “backward” projection. These molecular and hodological disruptions result in greater overall homogeneity of motor cortex output. Together, these results identify Lmo4 as a central developmental control over the diversity of motor cortex projection neuron subpopulations, establishing their area-specific identity and specialized connectivity.

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Section: Resultsmentioning

confidence: 99%

Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity

et al. 2013

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“…Indeed, in the embryonic spinal cord, GSK3-mediated phosphorylation of Neurog2 on Ser231/Ser234 results in the recruitment of the adaptor protein Ldb1 and the LIM homeodomain proteins Isl1 and Lhx3 into a complex that initiates motor neuron-specific gene expression (Ma et al, 2008). In this regard, it is interesting that Ldb1 and the LIM protein Lmo4 form a complex with Neurog2 that promotes neocortical neurogenesis, and that defects in neocortical neurogenesis are observed in Lmo4 mutants (Asprer et al, 2011). Currently, it is not known whether GSK3 plays a similar role in promoting Neurog2-Ldb1-Lmo4 complex formation in cortical progenitors.…”

Section: Temporal Regulation Of Neurog2 Activity By Gsk3 Phosphorylationmentioning

confidence: 99%

GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

Li¹,

Mattar²,

Zinyk³

et al. 2012

Journal of Neuroscience

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The neocortex is comprised of six neuronal layers that are generated in a defined temporal sequence. While extrinsic and intrinsic cues are known to regulate the sequential production of neocortical neurons, how these factors interact and function in a coordinated manner is poorly understood. The proneural gene Neurog2 is expressed in progenitors throughout corticogenesis, but is only required to specify early-born, deep-layer neuronal identities. Here, we examined how neuronal differentiation in general and Neurog2 function in particular are temporally controlled during murine neocortical development. We found that Neurog2 proneural activity declines in late corticogenesis, correlating with its phosphorylation by GSK3 kinase. Accordingly, GSK3 activity, which is negatively regulated by canonical Wnt signaling, increases over developmental time, while Wnt signaling correspondingly decreases. When ectopically activated, GSK3 inhibits Neurog2-mediated transcription in cultured cells and Neurog2 proneural activities in vivo. Conversely, a reduction in GSK3 activity promotes the precocious differentiation of later stage cortical progenitors without influencing laminar fate specification. Mechanistically, we show that GSK3 suppresses Neurog2 activity by influencing its choice of dimerization partner, promoting heterodimeric interactions with E47 (Tcfe2a), as opposed to Neurog2-Neurog2 homodimer formation, which occurs when GSK3 activity levels are low. At the functional level, Neurog2-E47 heterodimers have a reduced ability to transactivate neuronal differentiation genes compared with Neurog2-Neurog2 homodimers, both in vitro and in vivo. We thus conclude that the temporal regulation of Neurog2-E47 heterodimerization by GSK3 is a central component of the neuronal differentiation "clock" that coordinates the timing and tempo of neocortical neurogenesis in mouse.

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“…NeICD may serve a similar function and act as a transcription factor. It is interesting to note that LMO4 functions as a novel co-factor of Neurogenin 2 (NGN2) in the developing cortex [57]. LMO4 binds NGN2 to form a multiprotein transcription complex.…”

Section: Proteolysis Of Rgms Into Different Functional Protein Fragmentsmentioning

confidence: 99%

“…LMO4 binds NGN2 to form a multiprotein transcription complex. This complex is recruited to the E-box containing enhancers of NGN2 target genes, which regulate various aspects of cortical development and activate NGN2-mediated transcription [57]. It will be interesting to determine whether LMO4 and NeICD (and perhaps NGN2) form a transcription complex that regulates genes involved in axon growth.…”

Section: Proteolysis Of Rgms Into Different Functional Protein Fragmentsmentioning

confidence: 99%

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

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Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho) biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. RGMs: A Small Gene Family with Widespread EffectsGuidance molecules, initially observed to direct growing axons during embryogenesis [1], also have crucial roles in the morphogenesis and homeostasis of non-neuronal tissues by controlling a plethora of cellular processes, ranging from cell division and migration to differentiation and death. Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin. In this review, we discuss recent highlights in RGM research, from novel structural data to previously unexplored signaling mechanisms and cellular functions. Structural Insight into Ligand-Receptor InteractionsFor many years, RGMs posed a molecular puzzle because of a general lack of structural homologies to any known protein fold. Recent studies have shed light on their 3D structure and identified two ordered and disulfide-stabiliz...

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LMO4 functions as a co-activator of neurogenin 2 in the developing cortex

Cited by 35 publications

References 68 publications

Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity

Lmo4 Establishes Rostral Motor Cortex Projection Neuron Subtype Diversity

GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

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