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ACTH signalling and adrenal development: lessons from mouse models
Tatiana V Novoselova, Peter J King, Leonardo Guasti, Louise A Metherell, Adrian JL
Clark, Li F Chan
Affiliation
Centre for Endocrinology, William Harvey Research Institute, Barts and the London
School of Medicine, Queen Mary University of London, Charterhouse Square,
London EC1M 6BQ, UK.
Corresponding Author
Dr Li Chan
Centre for Endocrinology,
William Harvey Research Institute,
Barts and the London School of Medicine,
Queen Mary University of London,
Charterhouse Square,
London EC1M 6BQ, UK.
Tel: +44 207 882 8284;
Fax: +44 207 882 6197;
Email: l.chan@qmul.ac.uk
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Abstract
The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical
component of the hypothalamic-pituitary-adrenal axis. The importance of MC2R in
adrenal physiology is exemplified by the condition familial glucocorticoid deficiency
(FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R
mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP,
mutations of which account for ~20% of FGD, has provided insight into MC2R
trafficking and signalling. MRAP is a single transmembrane domain accessory
protein highly expressed in the adrenal gland and essential for MC2R expression
and function. Mouse models helped elucidate the action of ACTH. The Mc2r
knockout (Mc2r−/−) mice was the first mouse model developed to have adrenal
insufficiency with deficiencies in glucocorticoid, mineralocorticoid and
catecholamines. We recently reported the generation of the Mrap-/- mice which better
mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The
adrenal glands of adult Mrap−/− mice were grossly dysmorphic with a thickened
capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog
(SHH) pathway signalling. Collectively, these mouse models of FGD highlight the
importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex
maintenance and zonation.
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Hypothalamo-pituitary-adrenal axis
The hypothalamo-pituitary adrenal (HPA) axis dictates the production of
glucocorticoids secreted from the adrenal gland. Parvocellular neurosecretory
neurons within the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-
releasing hormone (CRH) and arginine vasopressin (AVP) (Sawchenko and
Swanson, 1985) into the hypophyseal portal circulation, which then acts on anterior
pituitary corticotroph cells to trigger secretion of adrenocorticotropic hormone
(ACTH) (1, 2). ACTH, a 39 amino acid peptide, is produced by cleavage of its
precursor protein, pro-opiomelanocortin (POMC). Other cleavage products of POMC
include α−, β−, γ-melanocyte stimulating hormones (MSH), β−endorphin, N-Terminal
peptide of proopiomelanocortin, lipotrophins and Met-enkephalin, Corticotropin-like
Intermediate Peptide (CLIP) (reviewed in (3, 4)). ACTH is released into the circulation
to act on peripheral sites, mainly the adrenal glands to stimulate glucocorticoid
hormone production. Glucocorticoids negatively feedback on the release of CRH and
AVP at the hypothalamus and ACTH at the pituitary, thus providing tight regulation of
cortisol production.
ACTH receptor/Melanocortin-2-receptor
The ACTH receptor also known as the melanocortin-2-receptor (MC2R), cloned in
1992 (5), is a critical component of the HPA axis and a member of the melanocortin
receptor family. Other members are MC1R, MC3R, MC4R and MC5R, the functions
of which were recently reviewed elsewhere (3). Unlike the other MCRs that also bind
melanocortins α−,β−, γ-MSH, MC2R is unique in that it only binds ACTH. In the
adrenal gland, MC2R is expressed in all zones of the adrenal cortex. Its principal site
of action is the zona fasciculata (ZF) in the generation of glucocorticoids in response
to ACTH, although action on the zona glomerulosa (ZG) and zona reticularis (ZR)
have been implicated in a number of physiological and disease states (6). In the
case of the ZG, ACTH can acutely stimulate aldosterone production and there is now
growing interest in the role of ACTH/MC2R in primary hyperaldosteronism (7, 8).
ACTH resistance syndromes and Familial Glucocorticoid Deficiency (FGD)
Much of what we know about MC2R has been through the study of the ACTH
resistance syndrome, Familial Glucocorticoid Deficiency (FGD). FGD is a rare
autosomal recessive condition clinically characterised by isolated glucocorticoid
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deficiency in the presence of normal mineralocorticoid function. FGD was first
reported in two siblings diagnosed with Addison’s disease without
hypoaldosteronism (9). Patients with FGD usually present in the neonatal period or
early childhood with symptoms of hypocortisolaemia such as hypoglycaemia, failure
to thrive, recurrent infections, collapse and seizures along with severe
hyperpigmentation due to the extra-adrenal action of excessive plasma ACTH on
MC1R in the skin melanocytes (10). Biochemically, FGD patients present with very
high plasma ACTH levels often greater than 1000 pg/ml paired with very low or
absent serum cortisol concentrations, hence the term ACTH resistance. Aldosterone
levels are usually unaffected although derangements have been reported in a subset
of patients (10-12). With the identification of additional FGD causative genes such as
steroidogenic acute regulatory protein (STAR), minichromosome maintenance 4
(MCM4), nicotinamide nucleotide transhydrogenase (NNT), thioredoxin reductase 2
(TXNRD2), cytochrome p450scc (CYP11A1), glutathione peroxidase 1 (GPX1),
peroxiredoxin 3 (PRDX3) and sphingosine 1-phosphate lyase (SGPL1), additional
phenotypes including permanent or evolving mineralocorticoid deficiency have been
reported, which has been recently reviewed elsewhere (13).
Loss of function mutations in MC2R and FGD type 1
The first loss of function missense mutation in MC2R, S74I, was identified in 1993
after candidate-gene sequencing of two siblings with FGD (14). Following this,
numerous loss-of-function mutations have been identified scattered along the whole
receptor (15), cementing the importance of MC2R in HPA biology. MC2R gene
mutations account for approximately 25% of all FGD cases (16, 17) and are referred
to as FGD type I (OMIM#202200). The majority of missense mutations result in a
misfolded protein and its retention in the endoplasmic reticulum while some genetic
defects affect ligand binding, signal transduction or lead to a truncated protein
product (3, 18). Patients harbouring MC2R mutations have been shown to have tall
stature (15, 19-21) along with advanced or dissociated bone age (22). The
mechanism for this phenomenon remains unclear but is not due to the insulin-like
growth factor I-growth hormone axis as this is normal (19). One potential explanation
is that the phenotype is due to high plasma ACTH levels acting on MCR in bone (23,
24). In support of this, ACTH has been shown to directly increase chondroprogenitor
cell proliferation in-vitro (25) and promote chondrocyte differentiation although the
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target MCR responsible for this action is uncertain (23). Interestingly, growth velocity
falls after the introduction of glucocorticoid replacement, during which plasma ACTH
levels often remain high. Another feature of absent adrenarche has also been
described (26) and, in conjunction with findings that have linked polymorphisms in
MC2R with age of adrenarche, highlights the importance of ACTH in the regulation of
adrenarche in children (27). The adrenal glands have been reported to be small in
FGD, with histopathology showing the absence of fasciculata or reticularis cells
together with disorganization of zona granulosa (ZG) cells (15). Recent data in
mouse models show that PKA signaling overactivation drives differentiation of a
reticularis-like zone in mice, supportive of the importance of ACTH in adrenal
androgen regulation (28).
Melanocortin-2-receptor accessory protein (MRAP) mutations and FGD type 2
Genetic studies of FGD patients with a normal MC2R, identified variants in the
C21orf61 gene. These variants would result in a truncation or complete absence of
the protein product, which was found to be highly expressed in the adrenal gland and
adipose tissue (16). In vitro studies revealed that this protein interacted with MC2R
and was the adrenal specific factor necessary for the transport of the receptor to the
plasma membrane and for the receptor signalling (16, 29-31) and hence was
renamed Melanocortin 2 Receptor Accessory Protein (MRAP). It is now known that
mutations in MRAP cause approximately 20% of all FGD cases and these are
termed FGD type 2 (32, 33). In comparison with FGD type 1, patients with MRAP
mutations present earlier with more severe disease. Tall stature is not seen, which is
probably a reflection of commencement of glucocorticoid replacement at an earlier
age (20). To date two FGD type 2 patients have been reported as requiring
fludrocortisone treatment, although it is unclear if this is a transient phenomenon
(34).
MRAP is a single transmembrane domain protein which is highly evolutionarily
conserved in the N-terminal and transmembrane regions (16). Human MRAP has
two isoforms produced by alternative splicing, MRAP-α (19 kDa) and MRAP-β (11.5
kDa), which differ in the C-terminus. The functional difference between the two
isoforms is unclear although differences have been reported in ACTH binding
capacity and cAMP generation have been reported (35). Interestingly, MRAP can
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form unique antiparallel transmembrane homodimers, which together with its
paralogue MRAP2 are as yet the only group of proteins known to do so in eukaryotic
cells. These MRAP homodimers form multimers with MC2R (36-38). The orientation
of the dimers is critical to function (36-38), moreover these antiparallel homodimers
are made early on in the biogenesis of the protein, are maintained and stable and in
a heterologous cell based system with a half-life of 2 hours (39). Although MRAP in
vitro binds and modulates the function of other melanocortin receptors (29), it is
unclear what physiological relevance this has at present.
Mouse models of FGD
The first mouse model of FGD was generated by Chida et al. in 2007 (40). The Mc2r
KO mouse model was the last member of the melanocortin receptor family to be
knocked out in mice. We recently generated a novel Mrap KO mouse model which,
like FGD, has isolated glucocorticoid deficiency. Both models are discussed in more
detail below.
Mc2r knockout mouse model
A mouse model of MC2R deficiency was generated by replacing the whole coding
region of Mc2r with a neomycin-resistance gene cassette (40), leading to complete
absence of Mc2r transcript in Mc2r-/- mice. On a C57BL/6J background the majority
of Mc2r-/- mice did not survive 48 hours after birth. Genotyping of 129 living mice at 4
weeks of age identified that only 9 (7%) were Mc2r-/-. It is worth noting that on a
B6/Balbc mix background approximately half Mc2r-/- mice survived to adulthood,
suggesting genetic modifiers at play (41). Detailed analysis demonstrated that Mc2r-
/- mice failed to produce glucocorticoids and developed profound neonatal
hypoglycemia resulting in high mortality levels during the first days of life. Moreover,
pups born to homozygous Mc2r null parents died before postnatal day 0.5 due to
lung failure, highlighting the importance of glucocorticoids in foetal lung maturation
(40). In addition to glucocorticoid deficiency, Mc2r-/- mice also had significantly lower
serum levels of aldosterone and catecholamines (40). Epinephrine levels were
significantly reduced in Mc2r-/- animals, whilst dopamine and norepinephrine
concentrations were unchanged. Examination of the adrenals of surviving adult mice
(never replaced with glucocorticoids) revealed dysmorphic glands with gross
hypoplasia of the ZF. Moreover, lipid droplets within the ZF cells were markedly
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reduced or absent, but cell nuclei were normal. However, the precise cell identity of
such ‘ZF’ cells is not known. Interestingly, the adrenal capsule in the Mc2r null mice
was thickened compared to Mc2r+/+ littermates. The majority of naturally occurring
MC2R loss-of-function mutations are missense mutations, many with residual
function (3, 18). Location and type of reported MC2R are summarised in a recent
review (3). As a demonstration of this, patients with missense MC2R mutations have
been known to present later on in childhood (20). Several more severe cases
including homozygous nonsense or frame shift mutations in MC2R have been
described to have hyponatraemia and/or disruption of renin-angiotensin-aldosterone
system (11, 12, 34). The majority of these are transient though permanent
fludrocortisone replacement have been described in several children (34). Hence,
although the complete KO of Mc2r in mice is not fully representative of human FGD
type 1, the model has nevertheless highlighted crucial actions of ACTH and/or
glucocorticoids during development.
Mrap knockout mouse model
We recently reported a Mrap KO (Mrap-/-) mouse model created by targeting the first
coding exon of Mrap, which led to complete absence of transcript and protein in
homozygote mice (42). Intercrossing heterozygote (Mrap+/-), also on a C57BL/6J
background, demonstrated high neonatal mortality. Out of 325 mice generated from
breeding Mrap+/- mice, only three Mrap-/- mice (<1%) survived until weaning (42). The
new-born pups born from heterozygous parents with normal adrenal function died
before postnatal day 1 and morphologically showed immature lungs and lack of
hepatic glycogen stores (42). Glucocorticoids treatment of pregnant Mrap+/- dams
rescued the phenotype, resulting in Mrap-/- mice born at the expected ratio of 25%.
This indicated that the observed high mortality in homozygous Mrap-/- newborns was
likely to be due to glucocorticoid deficiency rather than a direct effect of Mrap
deletion. Moreover, this phenotype highlights the importance of foetal rather than
maternal glucocorticoids in pre-partum neonatal adaptation in the Mrap-/- mouse.
The severity of this phenotype is consistent with the human data whereby FGD type
2 patients present soon after birth (20), thought to be due to the severity of the
mutations in MRAP that lead to complete disruption or absence of protein (20).
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Naturally occurring mutations in MRAP (location and type) have recently been
reviewed (3).
Adult Mrap-/- mice of both genders exhibited a grossly dysmorphic adrenal cortex
with the glucocorticoid synthesis pathway severely downregulated and unable to
produce glucocorticoids in the presence of high plasma ACTH levels. Surprisingly,
unlike the Mc2r-/- mice, circulating aldosterone and catecholamine levels were
unaffected (40, 42). The enzyme, phenylethanolamine N-methyltransferase (PNMT)
which is responsible for conversion of norepinephrine to epinephrine appeared to be
unaffected in Mrap-/- mice even though PNMT expression is known to be dependent
on glucocorticoid action. In contrast, PNMT is markedly reduced in Mc2r-/- (40). As
both knockout models are on a C57BL/6J background, one obvious difference is that
the Mrap-/- mice received relatively high doses of glucocorticoids between E17.5 until
weaning. This could contribute to the discrepancy in PNMT between Mc2r-/- and
Mrap-/- mice, especially in light of the fact that prenatal exposure to glucocorticoids
have been shown to lead to increased PNMT mRNA by RT-PCR and elevated
plasma epinephrine in adult rats (43). The discrepancy between aldosterone levels in
Mc2r-/- and Mrap-/- mice could be due to a number of possibilities, such as Mrap
independent aldosterone production (although in-vitro the MC2R is non-functional in
the absence of MRAP and MRAP protein expression closely mirrors that of MC2R in
the ZG), differences in salt intake between the 2 models (both rodent lines are fed
ad-libitum on a standard chow diet although, the salt content may differ) and finally
alterations of the renin-angiotensin-aldosterone system have also been reported in
animals exposed to glucocorticoids prenatally (44). Determining the mechanism of
such differences would further dissect adrenal ACTH action. Importantly however,
the absence of mineralocorticoid and catecholamine deficiency in Mrap-/- mice
makes it a unique model for studying FGD and isolated glucocorticoid deficiency.
Similar to the Mc2r-/- mouse model, the Mrap-/- adrenal capsule is thickened, which in
the Mrap-/- mice was shown to be due to an increased cell number, rather than
hyperplasia. This is of particular interest as the adrenal capsule and the subcapsular
region is known to contain adrenocortical stem/progenitor cells capable of dividing,
migrating centripetally and differentiating into mature steroid producing cell types
(45-47). In keeping with this, the absence of MRAP and therefore ACTH signalling,
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resulted in small adrenals with grossly deranged cortex zonation (discussed in
subsequent sections).
Other MRAP mouse models: Transgenic MRAP adipose tissue overexpression
mouse model
Prior to its renaming in 2005, MRAP was first identified as a putative novel
membrane protein selectively expressed during adipogenic conversion of 3T3-L1
cells and called FALP (fat tissue-specific low molecular weight protein) (48). The
protein expressed in both brown and white fat tissue and highly expressed during
adipogenesis (48, 49). More recently, the importance of MRAP in energy balance
was demonstrated using transgenic mice overexpressing MRAP in a fat specific
manner, under the control of the aP2 (adipocyte fatty acid binding protein) promoter
(50). These mice were shown to be protected against diet induced obesity and
diabetes, through enhancement of ACTH induced lipolysis. Therefore, this
demonstrated for the first time the emerging importance of MRAP in metabolism.
ACTH and adrenocortical renewal and zonation – contribution of Mrap and
Mc2r KO mouse models
Adrenocortical renewal and regeneration
The adrenal gland has a great capacity to respond to changes, renew and
regenerate. For example, activation of the HPA axis leads to expansion of the ZF
and increased expression of CYP11B1 and glucocorticoid production, whilst
suppression by dexamethasone leads to the contraction/atrophy of the ZF, reduced
CYP11B1 and glucocorticoid production (51). This is not specific to the ZF and
activation or inhibition of the renin-angiotensin-aldosterone system (ie triggered by a
diet low in sodium or treatment with ACE inhibitors, respectively) results in similar
changes in ZG morphology, CYP11B2 expression and aldosterone production (52).
This together with the appearance of compensatory growth of the contralateral
adrenal gland following unilateral adrenalectomy (53) demonstrates the dynamic
nature of the adrenal gland. Apart from remodelling, the adrenal gland can also
regenerate from residual adrenal capsular and adherent ZG cells in enucleation
studies (54, 55). Regeneration arises from cell proliferation and differentiation and is
associated with a thickened adrenal cortex (56).
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Role of ACTH in adrenal progenitor cell differentiation and maintenance
ACTH administration can induce ZF hyperplasia, with no effect on the ZG (57). More
recently, the localisation of Mc2r and Mrap to the undifferentiated zone (layer of
cyp11b1/b2 negative cells located between the ZG and ZF) in the rat adrenal (58,
59), suggested a role for ACTH in the differentiation of progenitor cells towards the
ZF phenotype in vivo. However, the data from remodelling experiments provides
somewhat conflicting evidence for the exact role of ACTH in adrenal progenitor cell
differentiation and maintenance. For example, some studies show that treatment
with dexamethasone blocks ZF proliferation and compensatory growth of the
contralateral gland following unilateral adrenalectomy (53, 60), whilst other studies
do not show this (61, 62). Hypophysectomy, with the complete removal of the
pituitary gland, blocks adrenal gland regeneration following enucleation (63) but does
not completely block compensatory growth (51, 64), and ACTH has even been
shown to inhibit this process (64). However, overall there is agreement that
hypophysectomy reduces the extent of compensatory growth suggesting the
presence of a pituitary factor. One possible factor is pituitary derived N-POMC,
derived from the POMC cleavage product pro--MSH. Neutralising antibodies against
pro--MSH inhibit both adrenal regeneration and compensatory growth. However,
pro--MSH has no direct mitogenic activity (65), hence it has been suggested that
further processing of pro--MSH to peptides such as N-POMC with mitogenic activity
is required (66). Evidence of the need for pituitary factors, including ACTH, comes
from work on POMC-/- animals that have complete absence of the POMC peptide
(67, 68). POMC-/- mice have adrenal glands that fail to proliferate postnatally leading
to atrophic adrenals which become undetectable with age (69). These adrenal
glands from POMC-/- animals can be rescued in size and function, following
transplantation into a wild-type recipient animal with physiological levels of all POMC
peptides. Interestingly, N-POMC cannot restore adrenal growth in POMC null mice
(70). However, high dose replacement of ACTH over several days restores POMC-/-
adrenal weight, morphology and corticosterone secretion (36), but it has been
suggested this is due to hypertrophy of the ZF rather than full regeneration of the
adrenal gland (71).
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Contribution of Mc2r and Mrap KO mouse models to understanding of adrenal
stem/progenitor cell differentiation and maintenance
The MC2R and MRAP KO mouse models add to our existing knowledge of the role
of ACTH in adrenal gland stem/progenitor cell differentiation and gland maintenance.
Assessment of the adrenal glands of Mrap-/- mice at embryonic day 17.5 shows that
the adrenal sizes are comparable to Mrap+/+ mice, derived from intercrosses of
heterozygous mice with normal HPA activity. However, when assessed at 8 weeks of
age the gland is significantly reduced in size with a thickened adrenal capsule (42).
One major issue is the separation of the effects of absent ACTH action and
glucocorticoid deficiency that are both present in adult Mrap-/- mice. After lifetime
glucocorticoid replacement the capsule reduced in thickness but still remained
significantly increased compared to wild-type littermate animals suggesting that both
glucocorticoid deficiency and absent ACTH action contribute to the expansion of the
stem cell niche in the adrenal gland, in keeping with some of the data described
above. Treatment of wild-type control mice with glucocorticoid resulted in
biochemically undetectable plasma ACTH coupled with corticosterone within the
normal range. These mice have a thickened capsule and thus taken together this is
highly suggestive that ACTH deficiency is a key contributor to capsule thickening.
The Mrap-/- mouse model also introduces some novel concepts in the growing
landscape of molecular pathways and factors involved in adrenal stem/progenitor
cell determination and differentiation. In fact this field is rapidly gaining pace with the
identification of new factors required for the adrenal homeostasis and zonation such
as RSPO3, EZH2 and ZNRF3 (72-74) and [reviewed in (46, 52)]. The WNT4/-
catenin and SHH pathways have been described to be key drivers of ZG identity
(75).
Cells that express WNT/-catenin, which co-express SHH and CYP11B2, normally
reside in the subcapsular region (40-42). It has been shown that cAMP/PKA,
activated by ACTH signalling in the adrenal gland, represses the WNT/beta-catenin
pathway to allow lineage conversion and correct adrenal cortex zonation (45).
Consistent with this, is the absence of ZF in the adrenals of Mrap-/- mice, whilst ZG is
intact and functional. However, the Mrap-/- mice identifies a concentric zone of cells
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between the ZG and adrenal medulla that are negative for Cyp11b2, Cyp11b1 and
20-HSD and hence not terminally differentiated ZG, ZF or ZR/fetal X-zone cells
respectively. These cells are WNT4/-catenin positive but negative for downstream
canonical targets of WNT signalling, LEF1 and DAB2 suggesting that canonical WNT
signalling is not active in these cells. Another option is that these cells were once
LEF1 and DAB2 positive and have subsequently lost some of ZG features. However,
the precise origin, fate and signalling potential within these cells are currently being
investigated.
SHH signalling is another key pathway regulating the differentiation of progenitor
cells into steroidogenic cells (76, 77). SHH positive cells in the stem cell niche, which
are located in the subcapsular region in mice and in the undifferentiated zone in rats,
have been shown through lineage tracing to differentiate into all cortical cell
populations in mice. The majority of Shh-descendants become ZG cells first and
then transition to ZF cells during centripetal migration (47, 76). In SHH KO mice, the
adrenal capsule is reduced to a single cell layer, suggesting that SHH could act as a
capsule cell mitogen/chemoattractant for noncapsule mesenchyme or to maintain
capsule progenitors (76). In the absence of MRAP, we see thickened capsule,
upregulated SHH expression and ectopic SHH expression throughout the cortex, no
longer restricted to the subscapular region. Together with the co-expression of
WNT4 and CYP11B2 this is suggestive that these cells have acquired ZG features.
Glucocorticoid treatment only partially attenuated this phenotype. Interestingly, the
levels of Gli1, which is a canonical target of SHH, were unchanged despite high SHH
expression. Determining the reason for this dissociation between high SHH and Gli1
which is unchanged as well as the co-ordination with other factors involved with
capsule thickness such as FGF signalling will be investigated in the future (Fig 1).
In conclusion, the mouse models of FGD have helped elucidate the action of ACTH
and glucocorticoids in adrenal development, progenitor cell renewal and zonation.
Further studies will focus on the role of ACTH signalling in physiology as well as how
this can be altered in disease states.
Declaration of interest
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We have no conflict of interest that could be perceived as prejudicing the impartiality
of the research reported.
Funding
The work reviewed was funded by The Medical Research Council UK
(MRC/Academy of Medical Sciences Clinician Scientist Fellowship Grant G0802796
to LF Chan).
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Figure Legends
Figure 1. Model illustrating the morphological alterations and pathway
deregulation in the adrenal gland of FGD type 2.
In the normal adrenal cortex, activation of SHH and WNT4 signalling results in
driving the expression of CYP11B2, DAB2 and LEF1 leading to a zona glomerulosa
(ZG) lineage. Activation of PKA due to the action of ACTH on MC2R/MRAP complex
suppresses WNT4 resulting in inhibition of CYP11B2, DAB2 and LEF1 and
differentiation into zona fasciculata (ZF) cells. In FGD type 2 (Mrap-/- mice) adrenal
glands, the lack of PKA activation results in complete absence of ZF and WNT4/SHH
accumulation outside the ZG, where WNT4 expression in such cells do not lead to a
functional ZG identity. Morphologically the ZG is expanded and is able to secrete
aldosterone. The adrenal medulla in FGD type 2 is morphologically intact and
secretes both epinephrine and norepinephrine.
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MC2R
MRAP
ACTH
PKA
MC2R
ACTH
PKA
ACTH
ACTH ACTH
ACTH
CYP11B1 (-)
CYP11B2 (-)
DAB2 (-)
LEF1 (-)
20-α-HSD (-)
CYP11B2 (+)
DAB2 (+)
LEF1 (+)
CYP11B2 (+)
DAB2 (+)
LEF1 (+)
capsular cell
zona glomerulosa cell
zona fasciculata cell
abnormal cells in FGD
Normal adrenal gland Adrenal gland in FGD type 2
CYP11B1 (+)
CYP11B2 (-)
DAB2 (-)
LEF1 (-)
WNT4/beta-catenin
SHH
*
*Activated Protein kinase A (PKA)
X zone
Inactive Protein kinase A (PKA)
PKA
PKA
*
PKA
ACTH
ACTH plasma ACTH
ALDO
ALDO
GC
adrenal medulla
CA
ALDO
GC
CA
aldosterone
glucocorticoids
catecholamines
CA
PNMT (+) PNMT (+)
X
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