HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.08-125971v1 23/7/2024    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lan, M. S. Articles by Breslin, M. B. Search for Related Content PubMed PubMed Citation Articles by Lan, M. S. Articles by Breslin, M. B.

Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation

Michael S. Lan^*,,,1 and Mary B. Breslin^*,,

^* Research Institute for Children, Children’s Hospital, New Orleans, Louisiana; and

Department of Pediatrics,

Department of Genetics, and

Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA

¹ Correspondence: Research Institute for Children, Children’s Hospital, 200 Henry Clay Ave., Research and Education Bldg., Rm. 2211, New Orleans, LA 70118, USA. E-mail: mlan{at}chnola-research.org

Zinc-finger transcription factors are DNA-binding proteins that are implicated in many diverse biological functions. INSM1 (formerly IA-1) contains five zinc-finger motifs and functions as a transcription factor. INSM1 protein structure is highly conserved in homologues of different species. It is predominantly expressed in developing neuroendocrine tissues and the nervous system in mammals. INSM1 represents an important player in early embryonic neurogenesis. In pancreatic endocrine cell differentiation, Ngn3 first activates INSM1 and subsequently NeuroD/β2. Conversely, INSM1 exerts a feedback mechanism to suppress NeuroD/β2 and its own gene expression. INSM1 gene ablation in the mouse results in the impairment of pancreatic endocrine cell maturation. Further, deletion of INSM1 severely impairs catecholamine biosynthesis and secretion from the adrenal gland that results in early embryonic lethality. Genetically, INSM1 acts as a downstream factor of Mash 1 and Phox2b in the differentiation of the sympatho-adrenal lineage. In the developing neocortex, mouse embryos lacking INSM1 expression contain half the number of basal progenitors and show a reduction in cortical plate radial thickness. Cell signaling studies reveal that INSM1 contributes to the induction of cell cycle arrest/exit necessary to facilitate cellular differentiation. INSM1 is highly expressed in tumors of neuroendocrine origin. Hence, its promoter could serve as a tumor-specific promoter that drives a specific targeted cancer gene therapy for the treatment of neuroendocrine tumors. Taken together, all of these features of INSM1 strongly support its role as an important regulator during neuroendocrine differentiation.—Lan, M. S., Breslin, M. B. Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation.

Key Words: Ngn3 • Mash 1 • zinc-finger transcription factor • pancreatic endocrine pathway • sympatho-adrenal lineage development • developing neocortex