Neurogenins
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Neurogenins, often abbreviated as Ngn, are a family of
Function
Neurogenins primarily govern the transition of neural progenitor cells to neurons by activating specific downstream genes associated with neuronal differentiation. Their involvement spans various stages of neurogenesis, including the determination of neural progenitor identity, cell cycle exit, and the acquisition of neuronal characteristics. Notably, Neurogenins influence the specification of different neuronal subtypes, contributing to the diverse array of neurons within the central and peripheral nervous systems.[2]
In
Regulation of neurogenic cascades
The activity of Neurogenins is intricately regulated by molecular pathways and environmental cues. Interaction with other transcription factors, such as proneural factors and Notch signaling, further refines the neurogenic cascades. Their spatiotemporal expression patterns and cross-regulation contribute to the exquisite precision required for proper neural development.[5][6]
Clinical implications
Neurogenins holds significant implications for clinical research, particularly in the context of
Neurogenin-1
Neurogenin 1 (Ngn1) is a Class-A
Neuronal differentiation
In E14 rats, when Ngn1 is present in the
Regulation by BMP
Regulation by LIF
In the presence of Ngn1, the
Glial differentiation
Along with supporting neuronal differentiation, when expressed in embryonic neural tissue, Ngn1 also acts to inhibit glial differentiation.[12] In the absence of Ngn1, the CBP/p300/Smad1 transcriptional co-activator complex is recruited to and binds to activated STAT1/3, which in turn causes the expression of GFAP, causing glial differentiation. In the presence of Ngn1, inhibition of gliogenesis occurs through Ngn1 binding to the CBP/p300/Smad1 transcriptional co-activator complex, recruiting it away from STAT1/3.[10]
Regulation by BMP
In cases of low levels of Ngn1, BMPs promote glial differentiation. Since Ngn1 is the limiting factor, CBP/p300/Smad1 is able to interact with STAT1/3 and induce gliogenesis.[10]
Regulation by Notch
Activation of the notch pathway, causes the inhibition of proneural bHLH genes, such as Ngn1, which allows for the CBP/p300/Smad1 to interact with STAT1/3 and induce gliogenesis.[10] Along with the embryonic rat, it was also seen in zebrafish that the repression of Ngn1 by Notch, promotes glial lineage in neural crest and central nervous system formation through the inhibition of neuronal differentiation.[1][13] In addition to the Notch pathway activating the transcriptional factors involved in the promotion of gliogenesis, it is possible that these same factors are involved in the inhibition of other fates.
Regulation by LIF
In the absence of Ngn1, the LIF pathway is able to activate STAT1/3, which allows for the promotion of GFAP transcription via the STAT binding site. The promotion of GFAP transcription induced glial differentiation.[10]
Neurogenin-2
Neurogenin 2 (Ngn2) is a bHLH transcription factor involved in both neurogenesis and neural specification. This protein binds to enhancer-box regulatory elements on the promoters of many genes related to neurogenesis and neural specification. For sufficient DNA binding, Ngn2 must form a
Neurogenesis and glial inhibition
Ngn2 is a transcription factor that both increases expression of proneural genes and drives neural fate by inhibiting expression of glial genes in
Neural specification
Mice lacking Ngn2 have fewer
Pan-neuronal fate
Heterodimerized Ngn2/enhancer protein complex can bind to enhancer boxes to promote transcription of genes related to a non-specified neuronal fate.[17]
V2 interneuron fate
When an enhancer box of a promoter that has been bound by the Ngn-2/enhancer protein complex is also bound by a dimer of the adaptor nuclear LIM interactor (NLI) bound to two LIM homeobox protein 3 (Lhx3), genes related to V2 interneuron identity are expressed.[17]
Motor neuron fate
A dimer of the adaptor NLI bound to two islet 1 (Isl1) proteins and each Isl1 is bound by Lhx3 is called the LIM-homeodomain (LIM-HD) transcription complex. When an enhancer box of a promoter that has been bound by the heterodimerized Ngn2/E-protein complex, the LIM-HD transcription complex is able to bind to drive expression of genes related to motor neuron fate, but only if Ngn2 has been properly phosphorylated.[17]
Ngn2 has two
Neurogenin-3
Neurogenin 3 (Ngn3) is another member of the bHLH family of transcription factors. Ngn3 functions in the differentiation of
Ngn3 is a crucial component in pancreatic development and plays a supporting role in intestinal as well as neuronal cell development. Studies have demonstrated that knockout of Ngn3 in mice leads to death shortly after birth possibly due to after effects of severe diabetes.[19] Further studies are taking place to investigate Ngn3's possible role as a treatment for diabetes and regeneration of cells in the pancreas.[19][21]
Neurogenin 3 (NGN3) is expressed by 2-10% of acinar and duct cells in the histologically normal adult human pancreas. NGN3+ cells isolated from cultured exocrine tissue by coexpressed cell surface glycoprotein CD133 have a transcriptome consistent with exocrine dedifferentiation, a phenotype that resembles endocrine progenitor cells during development, and a capacity for endocrine differentiation in vitro.[23] Human [24] and rodent [25][26][27][28][29][30][31][32][33] exocrine cells have been reprogrammed into cells with an islet cell-like phenotype following direct expression of NGN3 or manipulation that leads to its expression.
Phases of pancreatic development
The development of the pancreas is broken up into three phases, primary phase, secondary phase, and tertiary phase. Ngn3 is active in the primary and secondary phase. In the primary phase Ngn3 assists in
Modulation via notch pathway
The Notch pathway is one of the key modulators of Ngn3. The binding of
Downstream targets of Ngn3
NeuroD
Ngn3 can also activate the neurogenic differentiation factor 1(NeuroD1) like most of its other family members through the enhancer boxes present in its structure. Being that NeuroD1 is expressed along with Ngn3 in differentiating cells, it is considered one of the transcription factors downstream targets.[19]
Pax4
Another important target is
Nkx2.2
Another transcription factor that may be a downstream target of Ngn3 is Nkx2.2 because it is often coexpressed with it. Studies have shown that disrupting Nkx2.2 expression results in problems with α and β cell differentiation.[20][21]
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