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ARX/Arx is a homeodomain-containing transcription factor necessary for the specification and early maintenance of pancreatic endocrine α-cells. Many transcription factors important to pancreas development, including  ARX/Arx , are also crucial for proper brain development. Although null mutations of  ARX  in human patients result in the severe neurologic syndrome XLAG (X-linked lissencephaly associated with abnormal genitalia), the most common mutation is the expansion of the first polyalanine tract of  ARX , which results primarily in the clinical syndrome ISSX (infantile spasms). Mouse models of XLAG, ISSX and other human  ARX  mutations demonstrate a direct genotype-phenotype correlation in ARX-related neurologic disorders. Furthermore, mouse models utilizing a polyalanine tract expansion mutation have illustrated critical developmental differences between null mutations and expansion mutations in the brain, revealing context-specific defects. Although  Arx  is known to be required for the specification and early maintenance of pancreatic glucagon-producing α-cells, the consequences of the  Arx  polyalanine expansion on pancreas development remain unknown. Here we report that mice with an expansion mutation in the first polyalanine tract of  Arx  exhibit impaired α-cell specification and maintenance, with gradual α-cell loss due to apoptosis. This is in contrast to the re-specification of α-cells into β- and δ-cells that occurs in mice null for  Arx . Overall, our analysis of an Arx polyalanine expansion mutation on pancreatic development suggests that impaired α-cell function might also occur in ISSX patients.

Arx Polyalanine Expansion in Mice Leads to Reduced Pancreatic α-Cell Specification and Increased α-Cell Death