Neurogenins
Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.
In neural crest cells, the neurogenin family is essential for neurogenesis in the developing dorsal root ganglia and development of the sensory lineage.
Neurogenin-1
Neurogenin 1 is a Class-A basic-helix-loop-helix transcription factor that acts as a regulator for neuronal differentiation, and acts by binding to enhancer regulatory elements on genes that encode transcriptional regulators of neurogenesis. In order for Ngn1 to bind with high fidelity with genomic DNA, it must dimerize with another bHLH protein. Ngn1 is a proneural gene because its expression is seen prior to neural lineage determination, indicating it plays a role in neuronal differentiation.Neuronal differentiation
In E14 rats, when Ngn1 is present in the cerebral cortex, it binds to the CBP/p300/Smad1 transcriptional co-activator complex, which recruits it to the enhancer box upstream of the gene in the promoter for neuronal genes. Binding of Ngn1, to the enhancer box, induces the transcription factor NeuroD to bind to its own enhancer boxes, inducing the genes involved in neuronal differentiation.Regulation by BMP
signaling is responsible for the expression of the transcriptional co-activators CBP, p300, and Smad1. In the presence of Ngn1, BMPs promote neuronal differentiation in stem cells through binding of all endogenous CBP/p300/Smad1 to Ngn1, and being recruited toward the neuronal promoters, causing neuronal differentiation. In the embryonic forebrain, Ngn1 is associated with dorsal patterning and cell fate specification, with the patterning molecules and proneural proteins establishing the spatial domains of both proneural and homeodomain protein expression. This is critical for the initiation of neurogenesis.Regulation by LIF
In the presence of Ngn1, the leukemia inhibitory factor pathway is inhibited by Ngn1 blocking STAT activation. Normally, the STAT binding site promotes GFAP transcription through binding the STAT1/3 complex, which is activated through the LIF pathway.Glial differentiation
Along with supporting neuronal differentiation, when expressed in embryonic neural tissue, Ngn1 also acts to inhibit glial differentiation. 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.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.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. 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. 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.Neurogenin-2
Neurogenin 2 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 dimer with an enhancer protein.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 progenitor cells. This was observed in mice lacking Ngn2 and mash-1, which have more glia in the cortex and decreased capacity to generate neurons. Olig2 expression in what will become NPCs precedes Ngn2 and promotes its expression. During the switch from neural progenitor fate to glial fate, Ngn2 is downregulated and Nkx2.2, which inhibits proneural genes, is upregulated. Glial fate switch was reduced by inhibiting Nkx2.2 and Olig2 in neural progenitors while allowing the expression of Ngn2. The ability of Olig2 to induce expression of Ngn2 is reduced when Nkx2.2 is expressed.Neural specification
Mice lacking Ngn2 have fewer motor neurons and ventral interneurons, indicating that Ngn2 plays a role in specification of these neurons.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.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 bound to two LIM homeobox protein 3, genes related to V2 interneuron identity are expressed.Motor neuron fate
A dimer of the adaptor NLI bound to two islet 1 proteins and each Isl1 is bound by Lhx3 is called the LIM-homeodomain 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.Ngn2 has two serines, S231 and S234, which can be phosphorylated by glycogen synthase kinase 3. Phosphorylation of Ngn2 enables interaction with LIM-homeodomain proteins, leading to ventral neural fate and motor neuron specification. The importance of this phosphorylation was determined by using mice that express a mutated form of Ngn2 protein which has the serines from the previously mentioned phosphorylation sites mutated into alanines, which cannot be phosphorylated. These mutant mice have a decreased number of motor neurons and an increased number of V2 interneurons, suggesting that phosphorylation is necessary for driving expression of genes related to motor neuron fate but not V2 interneuron fate and non-specified neural fate.
Neurogenin-3
Neurogenin 3 is another member of the bHLH family of transcription factors. Ngn3 functions in the differentiation of endocrine pancreas cells. Although its key function is in the pancreas, intestinal cells and neural cells express Ngn3 as well. Several studies have highlighted the importance of Ngn3 for differentiation of endocrine cells. In mice, Ngn3 is present in cells as the pancreas begins to bud and glucagon cells are formed. There are several pathways that Ngn3 works through.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. Further studies are taking place to investigate Ngn3’s possible role as a treatment for diabetes and regeneration of cells in the pancreas.
Neurogenin 3 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. Human and rodent 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.