5 research outputs found
A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse
The transcription factor Gata1 is essential for the development of
erythroid cells. Consequently, Gata1 null mutants die in utero due to
severe anaemia. Outside the haematopoietic system, Gata1 is only expressed
in the Sertoli cells of the testis. To elucidate the function of Gata1 in
the testis, we made a Sertoli cell-specific knockout of the Gata1 gene in
the mouse. We deleted a normally functioning 'floxed' Gata1 gene in
pre-Sertoli cells in vivo through the expression of Cre from a transgene
driven by the Desert Hedgehog promoter. Surprisingly, Gata1 null testes
developed to be morphologically normal, spermatogenesis was not obviously
affected and expression levels of putative Gata1 target genes, and other
Gata factors, were not altered. We conclude that expression of Gata1 in
Sertoli cells is not essential for testis development or spermatogenesis
in the mouse
The POU factor Oct-6 is required for the progression of Schwann cell differentiation in peripheral nerves.
The POU transcription factor Oct-6, also known as SCIP or Tst-1, has been implicated as a major transcriptional regulator in Schwann cell differentiation. Microscopic and immunochemical analysis of sciatic nerves of Oct-6(-/-) mice at different stages of postnatal development reveals a delay in Schwann cell differentiation, with a transient arrest at the promyelination stage. Thus, Oct-6 appears to be required for the transition of promyelin cells to myelinating cells. Once these cells progress past this point, Oct-6 is no longer required, and myelination occurs normally
The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.
The genetic hierarchy that controls myelination of peripheral nerves by
Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger
Krox-20/Egr2 transcription factors. These pivotal transcription factors
act to control the onset of myelination during development and tissue
regeneration in adults following damage. In this report we demonstrate the
involvement of a third transcription factor, the POU domain factor Brn-2.
We show that Schwann cells express Brn-2 in a developmental profile
similar to that of Oct-6 and that Brn-2 gene activation does not depend on
Oct-6. Overexpression of Brn-2 in Oct-6-deficient Schwann cells, under
control of the Oct-6 Schwann cell enhancer (SCE), results in partial
rescue of the developmental delay phenotype, whereas compound disruption
of both Brn-2 and Oct-6 results in a much more severe phenotype. Together
these data strongly indicate that Brn-2 function largely overlaps with
that of Oct-6 in driving the transition from promyelinating to myelinating
Schwann cells
A cell type-specific allele of the POU gene Oct-6 reveals Schwann cell autonomous function in nerve development and regeneration
While an important role for the POU domain transcription factor Oct-6 in
the developing peripheral nerve has been well established, studies into
its exact role in nerve development and regeneration have been hampered by
the high mortality rate of newborn Oct-6 mutant animals. In this study we
have generated a Schwann cell-specific Oct-6 allele through deletion of
the Schwann cell-specific enhancer element (SCE) in the Oct-6 locus.
Analysis of mice homozygous for this allele (deltaSCE allele) reveals that
rate-limiting levels of Oct-6 in Schwann cells are dependent on the SCE
and that this element does not contribute to Oct-6 regulation in other
cell types. We demonstrate a Schwann cell autonomous function for Oct-6
during nerve development as well as in regenerating nerve. Additionally,
we show that Krox-20, an important regulatory target of Oct-6 in Schwann
cells, is activated, with delayed kinetics, through an Oct-6-independent
mechanism in these mice
Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling
The segregation and myelination of axons in the developing PNS, results from a complex series of cellular and molecular interactions between Schwann cells and axons. Previously we identified the Lgi4 gene (leucine-rich glioma-inactivated4) as an important regulator of myelination in the PNS, and its dysfunction results in arthrogryposis as observed in claw paw mice. Lgi4 is a secreted protein and a member of a small family of proteins that are predominantly expressed in the nervous system. Their mechanism of action is unknown but may involve binding to members of the Adam (A disintegrin and metalloprotease) family of transmembrane proteins, in particular Adam22. We found that Lgi4 and Adam22 are both expressed in Schwann cells as well as in sensory neurons and that Lgi4 binds directly to Adam22 without a requirement for additional membrane associated factors. To determine whether Lgi4-Adam22 function involves a paracrine and/or an autocrine mechanism of action we performed heterotypic Schwann cell sensory neuron cultures and cell typespecific ablation of Lgi4 and Adam22 in mice. We show that Schwann cells are the principal cellular source of Lgi4 in the developing nerve and that Adam22 is required on axons. Our results thus reveal a novel paracrine signaling axis in peripheral nerve myelination in which Schwann cell secreted Lgi4 functions through binding of axonal Adam22 to drive the differentiation of Schwann cells. Copyrigh