NCCs and SCPs play an important role in the development and functioning of various glands (Figure 2). Thus, a chimeric model of chicken/quail embryos has shown that most of the loose connective tissue of salivary glands originates from the neural crest (Nakamura, 1982). In addition, descendants of NCCs are found in the interlobular space and brain matter of the thymus, and also in the connective tissue of parathyroid glands (Suniara et al., 2000; Müller et al., 2008; Johansson et al., 2015).

The thymus has NC-derived mesenchyme which plays a crucial role in the growth and differentiation of glandular epithelium and T cells (Bockman and Kirby, 1984; Foster et al., 2008). In 12-day mouse embryo, NCCs migrated to the thymus region. Ablation of the neural crest in a region between the otic placode and the posterior part of somite 3 prevented the thymus formation or caused its underdevelopment. As the study showed, the number of cells positive to neural crest markers is reduced in thymus tissues, and the size of the forming thymus is directly related to the number of NCCs (Yamazaki et al., 2005).

Removal of perithymic mesenchyme from 12-day mouse embryo lobes blocked most lymphocytes at the CD4^–CD8^– stage of development. However, if the thymus lobes were left intact, generation of all T-cell subtypes occurred in them in vitro. Suniara and co-authors showed that mesenchymal cells directly regulate lymphopoiesis and that a lack of the intrathymic network of NC-derived fibroblasts and their process of extracellular matrix formation in the thymus leads to a decrease in lymphoid tissue development. Furthermore, it is the extracellular matrix that is necessary for integrin and/or cytokine interactions during the thymus development (Suniara et al., 2000).

Yamazaki and co-authors reported that multipotent cells originating from the neural crest are found in the embryonic thymus at stages E14.5 and E15.5, but are absent from the thymus at stage E17.5. The authors concluded that the presence of NC-derived cells in the thymus is important for its early embryonic development (Yamazaki et al., 2005).

In 2008, Foster and co-authors used Wnt1^CreR26^eYfp and Sox10^CreR26^eYfp transgenic mice to show that NC-derived cells populate the thymus primordiumand remain in it during the embryonic development and until 9–10 months of age. In addition, the authors showed that NC-derived cells differentiate into perivascular cells involved in the formation of the blood–thymus barrier (Foster et al., 2008).

In the same year, Müller and co-authors also found NC-derived cells in the adult thymus. NC-derived mesenchyme, according to the authors, may take part in performing specific functions of the blood–thymus barrier in the adult thymus, and are also part of the microenvironment providing maintenance of migrating cells (Müller et al., 2008).

Myoid cells of the thymus are suggested to originate from the neural crest. This hypothesis was advanced by Nakamura and Ayer-Le Liére (1986) whose study, as well as the first studies by Nicole Le Douarin on the neural crest, was based on a hybrid model of chicken embryo, where part of NCCs were replaced by NCCs of quail at the same stage of development. The NC origin of myoid cells in birds was confirmed subsequently, in 2015 (Bódi et al., 2015).

Early studies showed that calcitonin-producing thyroid cells originate from NCCs (Le Lievre and Le Douarin, 1970; Le Douarin and Le Lievre, 1970). This seminal study of neural crest cells, where the authors claimed that NCCs carry out invasion of ultimobranchial bodies prior to their fusion with the thyroid gland bud, was performed on chimeric avian embryos.

However, until 2007, there was no evidence whether the same process occurs in mammalian embryonic development. Kameda and co-authors showed that neither ectomesenchymal cells nor neural crest neuronal cells invade the ultimobranchial body primordium at stages E11.5–E12.5 (Kameda et al., 2007).

In 2015, Johansson and co-authors, using a genetic mouse model, confirmed and extended the previous idea that Wnt1⁺ NCCs contribute to the thyroid connective tissue development but are not a source of C cells in the mouse embryonic thyroid. Genetic tracing allowed the authors of this study to conclude that C cells are of endodermal origin (Johansson et al., 2015).

The anterior part of the pituitary gland originates from the adenohypophyseal placode (Ueharu et al., 2017). It was long believed that NCCs differentiate into interstitial cells of the adenohypophysis. The presence of interstitial cells (from NCCs) in the developing anterior lobe of the pituitary gland was analyzed using chimeric chicken/quail embryos (Couly and Le Douarin, 1987). Ablation of NCCs using the Wnt1^Cre and P0^Cre mouse strains showed that these cells are involved in pituitary vascularization, thus, giving rise to pericytes (Davis et al., 2016). The contribution of NCCs to the cerebral vasculature was previously described from mice by several research teams using the P0-Cre and human tissue plasminogen activator (HtPA)-Cre reporter lines (Pietri et al., 2003; Nishiyama et al., 2012).

Ueharu et al. (2018), using genetic tracing in a mouse P0-Cre/EGFP model, showed that NCCs invade the adenohypophysis in several stages (waves). In a study by Kato with co-authors based on a S100β/GFP-TG rat model, NCCs populated the pituitary gland in several successive waves (Kato et al., 2021). The first wave was detected in mice at stage E9.5, when the pituitary primordium begins to form with adenohypophyseal placode cells; the second wave of invasion was observed at stage E14.5, when vasculogenesis proceeds from the Atwell’s recess. Genetic tracing of NCCs showed that they are capable of differentiating into both pericytes and all hormone-producing cell lineages of the adenohypophysis. According to the results of this study, NCCs contribute to pituitary organogenesis and vasculogenesis together with placode cell derivatives. In addition, the same team of researchers, using a different model, confirmed that SOX10-positive cells found in the pituitary gland are positive to another marker of NCCs, p75NTR. Immunohistochemical staining with antibodies to SOX10 during the pituitary development demonstrated the spatial and temporal pattern of localization of SOX10-positive cells in the posterior, intermediate, and anterior lobes (Ueharu et al., 2018).

As Kirchgessner and co-authors showed on a model of rat intestine and pancreas explants, NCCs migrate to the intestine, and only after that continue their migration to the pancreas, where they give rise to intrapancreatic ganglion neurons (Kirchgessner et al., 1992). It was also reported that NCCs migrating into the pancreas differentiate into sympathetic, parasympathetic, and sensory neurons (Ahren, 2000).

Descendants of NCCs are known to be involved in pancreatic development. Smith (1975) showed that these cells are capable of differentiating into Schwann cells that surround the islets of Langerhans.

Signals from NCCs regulate the mass proliferation and maturation of pancreatic beta cells (Nekrep et al., 2008; Plank et al., 2011). Co-culturing of NCCs and pancreatic islets in vitro promoted the regeneration of functional beta cells (Olerud et al., 2009). NCC descendants migrating to the pancreatic region may be important for maintaining beta cell function, development, and maturation. Shimada et al. (2012) reported that NCC descendants maintain beta cell signaling at each stage of the pancreatic development. An earlier study showed that by 15.5 days post-coitum, neural crest-derived neurons were localized close to insulin-expressing clusters of cells and then contacted 98.9% of beta cell clusters on postnatal day 1 (Plank et al., 2011). However, the results obtained by the team of Shimada with co-authors showed that neural crest derivatives at late stages of embryonic development are closer to alpha cells than to beta cells in the pancreas. According to them, NCC derivatives surround the endocrine cells of the pancreas and influence them through juxtacrine or paracrine regulation (or both) (Shimada et al., 2012).

A number of studies carried out in the 1970s to elucidate the possible embryonic origin of pancreatic endocrine cells from NCCs were largely based on chimeric chicken/quail embryo models. Pictet et al. (1976), who investigated the origin of the islets of Langerhans, cultured rat embryos in vitro at early stages of development after removal of the neuroectoderm primordium. Interestingly, the pancreas developed under these conditions, and insulin-producing cells were observed. According to Andrew (1976) who used the chimeric model described above, neuroectodermal cells from the trunk never migrate to the pancreas. Andrew et al. (1986) and Fontaine and Le Douarin (1977), based on the same chimeric model, showed that NCCs migrating to the pancreas originated from the vagal region but did not differentiate into insulin-, glucagon-, somatostatin-, or avian pancreatic polypeptide- (APP) producing cells.

In 1999, Aumüller and co-authors found for the first time that human prostate neuroendocrine cells have a neurogenic origin, distinct from that of secretory and basal cells of the gland (Aumüller et al., 1999). Using a Wnt1-Cre/ROSA26-YFP mouse model and abortive human material, Szczyrba and co-authors showed that 64% of mouse prostate neuroendocrine cells originate from NCCs (Szczyrba et al., 2017).

Single NCCs colonize the ovary at around E16.5 and differentiate into neurons and glia that give rise to the entire ovarian neural network. In contrast, NCCs do not infiltrate the testis. Theca cells, derived from the mesenchyme and steroidogenic cells of the ovary, also migrate into the ovary between E17.5 and P5 in a pattern very similar to that of the ovarian innervation development. In the ovary, nerve projections are located in close proximity to the theca cell layer of growing follicles, where they may be involved in stimulating theca or smooth muscle cells during the follicle growth and ovulation (McKey et al., 2019).

Chromaffin cells of the adrenal medulla originate from Schwann cell precursors (SCPs) that are descendants of NCCs (Furlan et al., 2017).

SCPs migrate along axons of cholinergic preganglionic neurons in the spinal cord, moving towards the developing sympathoadrenal primordium (Lumb et al., 2018). Upon reaching the rudiment (stages E11.5 and E12.5 in mouse), the SCPs begin to differentiate into chromaffin cells of the adrenal medulla, passing through a transition state referred to as the “bridge”. It is worth mentioning that most SCPs do not transdifferentiate subsequently but continue the transformation into satellite glial cells located next to neuronal bodies in peripheral ganglia or into Schwann cells covering peripheral nerves. A little later in development, some of the immature, nerve-associated Schwann cells begin to myelinate, while the rest remain dormant on nerves as Remak cells or non-myelinating Schwann cells (Jessen and Mirsky, 2005; Jessen et al., 2015).

A study based on transgenic mice showed that organ of Zuckerkandl cells can also originate from nerve-associated SCPs, similarly to adrenal chromaffin cells (Furlan et al., 2017).

Cells originating from NCCs were found in the submandibular salivary glands of adult mice. These cells form a kind of “islets” inside the glands and express various markers characteristic of NCCs such as Sox10 and Ednrb. Furthermore, as was shown on a Wnt1-Cre/R26R lacZ mouse model, the mesenchyme of embryonic submandibular salivary glands originates entirely from the cranial region of the neural crest (Jaskoll et al., 2001; Takahashi et al., 2014).

Neural crest cells (NCCs) are often referred to as the “fourth germinal layer” because of their broad potential to differentiate into a variety of adult cells, ranging from mesenchymal cells to various types of neurons. The emergence of NCCs in the course of evolution has contributed to the generation of a large number of new structures or to the increased complexity of existing ones in chordate organisms. NCCs take an active part in the development of various systems of the body, including the formation of endocrine glands, regulating their proper embryonic development and giving rise to neuroendocrine cells, neurons, and various types of glial cells. Schwann cell precursors, being also multipotent descendants of NCCs, are involved in the gland formation, but many questions as to their role in endocrine embryogenesis remain unaddressed. Despite the ongoing active research in the field of genome evolution and the development of the New Head hypothesis, the origin and evolution of the neural crest and its descendants remains not entirely clear.

Understanding the cellular mechanisms of various organs formation during embryonic development is extremely important for compiling a complete picture of normal embryogenesis, as well as for identifying targets in the treatment of diseases of the adult body and searching for a cellular source for replacement therapy. NCCs and SCPs are among the key participants in the formation of various parts of the nervous and endocrine systems, which makes them an important object for further study.