Mind bomb 1 is required for pancreatic β-cell formation

Area of Science:

• Developmental Biology
• Endocrinology
• Cell Biology

Background:

• Notch signaling regulates pancreatic progenitor cell differentiation and proliferation.
• Nkx6 transcription factors and Ptf1a antagonistically segregate multipotent progenitor cells (MPCs).
• Proximal MPCs give rise to duct and beta-cells, while distal MPCs form acinar cells.

Purpose of the Study:

• To investigate the signals regulating proximodistal (P-D) patterning in the developing pancreas.
• To determine the role of Mind bomb 1 (Mib1) in pancreatic P-D patterning and beta-cell formation.

Main Methods:

• Endoderm-specific inactivation of Mib1 in mice.
• Conditional expression of dominant-negative Mastermind-like 1 (Maml1).
• Conditional inactivation of the Notch target gene Hes1.

Main Results:

• Mib1 inactivation resulted in loss of Nkx6-1(+)Ptf1a(-) and Hnf1β(+) cells, and subsequent loss of endocrine progenitors and beta-cells.
• Absence of Mib1 led to proximal cells adopting a distal fate, indicated by increased Nkx6-1(-)Ptf1a(+) and amylase(+) cells.
• Interfering with Notch signaling via Maml1 or Hes1 inactivation similarly disrupted P-D patterning and suppressed beta-cell formation.

Conclusions:

• Mind bomb 1 (Mib1) is essential for correct pancreatic proximodistal (P-D) patterning.
• Mib1 activity is required for the formation of beta-cell progenitors and subsequent beta-cell development.
• Notch signaling is iteratively utilized to ensure proper P-D patterning and adequate beta-cell formation during pancreatic development.