Address for correspondence: Klaus Unsicker, Department of Neuroanatomy, Institute for Anatomy and Cell Biology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 307, D-69120 Heidelberg, Germany. Voice: +49-6221-54-8227; fax: +49-6221-54-5604.
klaus.unsicker{at}urz.uni-heidelberg.de
Ann. N.Y. Acad. Sci. 971: 554-559 (2002).
The developmental diversification of neural crest-derived sympathoadrenal
(SA) progenitor cells into neuroendocrine adrenal chromaffin
cells and sympathetic neurons has been thought to be largely
understood. Based on two decades of
in vitro studies with isolated
SA progenitor and chromaffin cells, it was widely assumed that
chromaffin cell development crucially depends on glucocorticoid
hormones provided by adrenal cortical cells. However, analysis
of mice lacking the glucocorticoid receptor has revealed that
the chromaffin cell phenotype develops largely normally in these
mice, except for the induction of the adrenaline synthesizing
enzyme phenylethylamine
N-methyl transferase. In a search for
novel candidate genes that might be involved in triggering the
sympathetic neuron/chromaffin cell decision, we have studied
putative contributions of transforming growth factor (TGF)-
,
BMP-4, and the transcription factor MASH-1, molecules with distinct
expressions in SA progenitor cells, in their migratory pathways
and final destinations. TGF-ß2 and -ß3 and
BMP-4 are highly expressed in the wall of the dorsal aorta and
in the adrenal anlagen during and after immigration of SA progenitors
but expressed at much lower levels in sympathetic ganglia. We
found that neutralizing antibodies against all three TGF-ß
isoforms applied to the chorionic-allantoic membrane (CAM) of
quail embryos interfere with proliferation of immigrated adrenal
chromaffin cells but do not affect their specific neuroendocrine
ultrastructural phenotype. Grafting of noggin-producing cells
to the CAM, which scavenges BMPs, interferes with visceral arch
and limb development but does not overtly affect the chromaffin
phenotype. The transcription factor MASH-1 promotes early differentiation
of SA progenitors. Mice deficient for MASH-1 lack sympathetic
ganglia, whereas the adrenal medulla previously has been reported
to be present. We show here that most adrenal medullary cells
in MASH-1
-/- mice identified by Phox2b immunoreactivity lack
the catecholaminergic marker tyrosine hydroxylase. More surprisingly,
most cells do not contain chromaffin granules and display a
neuroblast-like ultrastructure and show strongly enhanced expression
of c-RET comparable to that observed in sympathetic ganglia.
Together, our data suggest that TGF-ßs and BMP-4 do
not seem to be essential for chromaffin cell differentiation.
In contrast with previous reports, however, MASH-1 apparently
plays a crucial role in chromaffin cell development.
