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Table 2 Function of the main genes involved in β-cell differentiation

From: Stem cells differentiation into insulin-producing cells (IPCs): recent advances and current challenges

Gene

Function

References

nanog (Nanog homeobox)

Critical for early embryogenesis and for ESC pluripotency

[83, 84]

oct4 (POU domain, class 5, transcription factor 1

sox2 (SRY (sex determining region Y)-box 2

foxa2 (forkhead box A2)

Necessary for proper endoderm formation and pdx1 expression. Also required for regulated insulin secretion in mature β-cells—regulates the expression of important genes for glucose sensing in pancreatic β-cells and glucose homeostasis

[85,86,87,88,89]

cxcr4 (chemokine (C-X-C motif) receptor 4)

Required for proper β cells generation – it is a key marker of definitive endoderm, controlling cells migration during gastrulation

[90, 91]

sox17 (SRY (sex determining region Y)-box 17

Controls segregation of liver, biliary system, and pancreas; regulates insulin trafficking and secretion in β-cells

[92,93,94,95]

nkx6.1 (NK6 homeobox 1)

Directly targeted genes involved in insulin biosynthesis (Slc30a8 and Ero1lb), glucose transporter 2 (Glut2), and glucose metabolism

[96]

pdx1 (pancreatic and duodenal homeobox 1

Mainly involved in glucose-dependent regulation of insulin gene expression. Also necessary for the activation of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide and GLUT2

[97, 98]

ptf1a (pancreas associated transcription factor 1a

Required for exocrine cell formation—activates an acinar cell genes repertoire. Has a complex set of interactions with Notch downstream intercellular mediators to regulate target patterning genes and acinar-specific genes

[99,100,101,102]

sox9 (SRY-box transcription factor 9)

Necessary for regulation of pancreatic specification, differentiation and duct morphology

[103,104,105,106,107]

Cg (Chromogranin) A

Constitute the regulated pathway of protein hormone secretion including all four pancreatic peptide hormones and gastrin. It is involved in the generation of secretory granules and is considered a pan-endocrine marker

[108, 109]

ngn3

(neurogenin 3)

Endocrine formation key regulator—induces the expression of endocrine genes such as neuroD1, nkx2.2, nkx6.1, pax4, pax6 and isl1

[110,111,112]

neuroD1

(neurogenic differentiation 1)

Involved in islet growth, proliferation and endocrine differentiation in pancreatic progenitors. Activates IA1 (Insulin Associated 1), a zinc finger protein that appears to be important in executing the endocrine differentiation process. Can activate the pax6 gene

[113,114,115,116]

nkx2.2

(NK2 homeobox 2)

Necessary for β-cell precursors to express nkx6.1 and ins. Also binds to and activates mafa

[117,118,119]

pax4

(paired box gene 4)

Directs formation of β and δ cells. Acts as a transcriptional repressor, being especially effective for ghrelin expression and pax6-mediated glucagon expression

[120,121,122,123,124]

ins (insulin)

Provides instructions for producing the insulin hormone

[125]

mafa (v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A)

Controls and activates insulin gene expression

[126, 127]

mafb (v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B)

Appears to be a key regulator of α- and β-cell maturation, since Mafb binds to and activates the mafa gene, causing a transition from mafb to mafa expression in insulin + cells as they transition from immature to mature β cells

[128]

Glut2 / SLC2A2

(solute carrier family 2 member 2)

An integral plasma membrane glycoprotein of islet β-cells that mediates facilitated bidirectional glucose transport

[129]