Loss of Myt1 function partially compromises endocrine islet cell differentiation and pancreatic physiological function in the mouse.
Myelin transcription factor 1 (Myt1) is one of the three vertebrate C2HC-type zinc finger transcription factors that include Myt1 (Nzf1), Myt1L (Png1), and Myt3 (Nzf3, St18). All three paralogs are widely expressed in developing neuronal cells. Yet their function for mammalian development has not been investigated directly. Here we report that only Myt1 is expressed in the embryonic pancreas, in both endocrine progenitors and differentiated islet cells. Myt1(-/-) animals die postnatally, likely due to confounding effects in multiple tissues. The endocrine tissues in the embryonic Myt1(-/-) pancreas contained abnormal islet cells that expressed multiple hormones; although hormone levels were normal. We also created pancreas-specific Myt1 knockout mice. These mutant animals had no obvious physical defects from their wild-type littermates. Male mutant animals had reduced glucose-clearing abilities and abnormal multi-hormone-expressing cells present in their endocrine islets. In addition, they also had reduced Glut2 expression, and attenuated glucose-induced insulin secretion in the adult islets. Surprisingly, the expression of the Myt1 paralogs, Myt1l and Myt3, was induced in the embryonic Myt1(-/-) pancreas. The consequences of Myt1 inactivation in the developing pancreas could be masked by activation of its paralogs, Myt1l and Myt3. These findings suggest Myt1 is involved in proper endocrine differentiation and function.
Wang
Sui
S
Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Avenue South, Room 4128, Nashville, TN 37232, USA.
Zhang
Jia
J
Zhao
Aizhen
A
Hipkens
Susan
S
Magnuson
Mark A
MA
Gu
Guoqiang
G
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005947:Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D019426:Integrases; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C489726:Myt1 protein, mouse; C581556:Myt3 protein, mouse; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C045073:Cre recombinase