2023 Project 5
Student Projects 2023: 1 Patterning neural border and NC | 2 NPB NEUcrest | 3 EMT and NC | 4 miRNA and NC | 5 Adrenal Gland and NC | 6 Melanocyte & Melanoma | 7 Neurocristopathies | Neural Crest
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The Neural Crest and Adrenal Gland Development in Vertebrates
Adrenal Gland Development
Adrenal glands are key hormonal regulators of the human body, governing major physiological processes such as the body’s fluid homeostasis, as well as secondary sexual development and the stress response (Kempná and Flück 2008). The mammalian adrenal glands sit on top of the kidneys, composed of two distinct embryonic endocrine tissues: the outer adreno-cortical layer which surrounds the inner adrenal medulla, containing neurosecretory chromaffin cells (Kanczkowski, Sue et al. 2017). The two main sets of essential hormones produced by the adrenals are steroid hormones, synthesised from cholesterol by cells of the cortex, and catecholamines adrenaline and nor-adrenaline that are secreted and released by chromaffin cells during the fight-or-flight response (Kanczkowski, Sue et al. 2017). Chromaffin cells were long thought to be directly derived from migrating trunk neural crest cells. However, research in recent years has shown that chromaffin cells are mostly derived from nerve-associated glial progenitor cells, named Schwann Cell Precursors (SCPs), which are themselves direct neural crest derivatives (Furlan, Dyachuk et al. 2017, Lumb, Tata et al. 2018, Kameneva, Artemov et al. 2021, Kastriti, Faure et al. 2022).
During embryonic development in mice, early neural crest cells, after delaminating from the dorsal neural tube, migrate ventrally towards the dorsal aorta, and form the SCPs on the nerve surfaces and cells building suprarenal and other sympathetic ganglia (Furlan, Dyachuk et al. 2017, Tsubota and Kadomatsu 2018). Therefore, the migratory neural crest-derived sympathoadrenal progenitors form the sympathetic chain, paraganglia (including the suprarenal ganglion), and possibly a few chromaffin cells that inhabit the adrenal anlagen (Furlan, Dyachuk et al. 2017, Bechmann, Berger et al. 2021). A bit later, nerve-riding SCPs are recruited to produce chromaffin cells via a transitional bridge stage, also generating intra- and some extra-adrenal sympathetic neurons (Kastriti, Kameneva et al. 2019). This sympathoadrenal fate-progression is driven by a network of specific transcription factor genes, which include Ascl1, Phox2a/b, Hand2, Gata2/3 and Insm1 (Kastriti, Kameneva et al. 2020, Bechmann, Berger et al. 2021). Their upregulation is driven by paracrine bone morphogenetic proteins (BMPs) in the dorsal aorta area (Saito, Takase et al. 2012, Kastriti, Kameneva et al. 2020).
Although directly migrating neural crest cells might potentially contribute a small portion of chromaffin cells to developing adrenal glands, the majority of chromaffin cells arise from SCPs, which attach to preganglionic sympathetic axons that innervate the developing adrenal gland (Furlan, Dyachuk et al. 2017, Kastriti, Faure et al. 2022). Such axons of the preganglionic neurons of the spinal cord extend towards developing internal organs and are guided by class 3 SEMPAPHORINS (SEMA3s) and their receptors NEUROPILIN-1 (NRP1) and NEUROPILIN-2 (NRP2) as soon as they are in close contact to the sympathoadrenal primordium (Lumb, Tata et al. 2018). Once there, the SCPs detach from the preganglionic axons and differentiate into chromaffin cells and intermedullary sympathetic neurons, through a transitory ‘bridge’ transcriptional stage representing a progenitor cell types with its own unique transcriptional program (Furlan, Dyachuk et al. 2017, Kastriti, Faure et al. 2022, Kastriti, Faure et al. 2022). After a short period of differentiation, chromaffin cells (in mice), all express tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), two enzymes necessary for adrenaline synthesis (Kastriti, Kameneva et al. 2020). Chromaffin cells can then further be characterised into noradrenaline producing cells and some adrenaline producing chromaffin cells, which are distinguished by the expression of phenyl-ethanolamine-N-methyltransferase (PNMT) (Bechmann, Berger et al. 2021, Kastriti, Faure et al. 2022). The versatile and heterogenous nature of the NC can also contribute to malignancy and tumour metastasis (Maguire, Thomas et al. 2015). Tumours associated with the adrenal medulla and paraganglia include catecholamine-secreting tumours pheochromocytomas (PCCs) and paragangliomas ( PGCs), as well as Neuroblastoma: a paediatric cancer found along the peripheral nervous system, commonly emerging near the AG and is responsible for approximately 15% of cancer-related deaths in children(Maguire, Thomas et al. 2015, Wulf, Moreno et al. 2021).
Vertebrate Comparison of Adrenal Gland Composition
Adrenal gland structure and development is not identical among vertebrate species and to this day, is not well understood. While in mammals the zonation of the cortical structure can differ slightly, as seen between human and mice, the clear separation of the adrenal homologues into cortex and medulla is not always as easily distinguishable in lower vertebrates (Kastriti, Kameneva et al. 2020). While in amniotes (birds and mammals), adrenal glands sit on top of the kidney, amphibians and reptiles don’t have a clear adrenal structure, but rather chromaffin cells and steroidogenic cells that are intermingled with the kidney (Kang, Marin et al. 1995, Furlan, Dyachuk et al. 2017, Mcmillan and Harris 2018)(Figure 2). An example of this, are zebrafish (teleost) that have a so-called interrenal gland, that develops within the kidney and is made up of intermingled steroidogenic interenal and chromaffin cells, functionally equivalent to the adrenal cortex and medulla in mammals (Chou, Lin et al. 2016, Kastriti, Kameneva et al. 2020) .
Figure 2: Differences and similarities among various vertebrate adrenal tissues, adapted from Mcmillan and Harris 2018. Black cells show chromaffin cell tissue while grey represents steroidogenic tissue. In amniotes (birds and mammals) the adrenal glands sit on top of the head kidney. Anurans have their AG on the ventral side of the kidney with chromaffin and steroidogenic cells intermingled. This is similar to the interrenal gland structure in teleosts, where these cells sit at the top of the kidney.
References
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