General and Comparative Endocrinology xxx (2014) xxx–xxx

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Extrapituitary growth hormone and growth? Steve Harvey ⇑, Marie-Laure Baudet 1 Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

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Article history: Available online xxxx Keywords: Growth hormone Pituitary Extrapituitary Embryo Autocrine Paracrine

a b s t r a c t While growth hormone (GH) is obligatory for postnatal growth, it is not required for a number of growthwithout-GH syndromes, such as early embryonic or fetal growth. Instead, these syndromes are thought to be dependent upon local growth factors, rather than pituitary GH. The GH gene is, however, also expressed in many extrapituitary tissues, particularly during early development and extrapituitary GH may be one of the local growth factors responsible for embryonic or fetal growth. Moreover, as the expression of the GH receptor (GHR) gene mirrors that of GH in extrapituitary tissues the actions of GH in early development are likely to be mediated by local autocrine or paracrine mechanisms, especially as extrapituitary GH expression occurs prior to the ontogeny of pituitary somatotrophs or the appearance of GH in the circulation. The extrapituitary expression of pituitary somatotrophs or the appearance of GH in the circulation. The extrapituitary expression of GH in embryos has also been shown to be of functional relevance in a number of species, since the immunoneutralization of endogenous GH or the blockade of GH production is accompanied by growth impairment or cellular apoptosis. The extrapituitary expression of the GH gene also persists in some central and peripheral tissues postnatally, which may reflect its continued functional importance and physiological or pathophysiological significance. The expression and functional relevance of extrapituitary GH, particularly during embryonic growth, is the focus of this brief review. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Pituitary growth hormone (GH), as its name suggests, is synonymous with postnatal growth. Indeed, it is well established that a pituitary GH deficiency or a defect in tissue GH receptor (GHR) signaling results in dwarfism, whereas an excess of pituitary GH secretion results in gigantism in juveniles or acromegaly in adults. Despite this recognized role, it is generally believed that embryonic or early fetal growth is independent of pituitary GH (Waters and Kaye, 2002). This possibility is supported by the finding that decapitation of the pig fetus at 45 d of gestation does not alter body weight when compared to controls at 110 d of gestation (Kraeling et al., 1978; McCusker and Campion, 1990). Similarly, the hypophysectomy of fetal lambs does not reduce their body weight or body length at term (Parkes and Hill, 1985; Enemar, 2003). Hypophysectomy also does not reduce the weights of the brain, liver or kidney in fetal lambs, suggesting that the growth of these organs is not dependent upon pituitary GH or other pituitary hormones (Deayton et al., 1993). Embryonic or early fetal ⇑ Corresponding author. Fax: +1 780 492 3956. E-mail address: [email protected] (S. Harvey). Current address: Center for Integrative Biology (CIBio), University of Trento, 38123 Mattarello, Italy 1

growth are thus thought to reflect growth-without-GH syndromes that are dependent upon other local growth factors instead of pituitary GH (Geffner, 1996; Phillip et al., 2002). The extrapituitary expression of the GH gene is, however, likely to be one of these local growth factors in early development, before the onset of pituitary GH secretion. The extrapituitary expression of the GH gene also persists in some peripheral tissues postnatally, which may reflect its continued functional importance and physiological or pathophysiological significance. The expression and functional relevance of extrapituitary GH, particularly during embryonic growth, is the focus of their brief review.

2. Pituitary GH gene expression The GH gene was thought to be specifically expressed in pituitary somatotrophs in response to the pituitary specific expression of its Pit-1 transcription factor. Indeed, ‘‘no other site of GH synthesis’’ was thought to exist (Karin et al., 1990). It is, however, now known that GH gene expression is not confined to pituitary somatotrophs and indeed it occurs widely in many extrapituitary tissues (Harvey, 2010). This widespread expression party reflects the distribution of Pit-1 which is not confined to the pituitary gland, as once thought (Harvey et al., 2000a). Moreover, while 0016-6480/Ó 2014 Elsevier Inc. All rights reserved.

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Pit-1 was thought to be obligatory for GH expression, it is now known that GH expression is Pit-1 independent in many sites (Harvey et al., 2000a) and GH expression even occurs outside the pituitary gland, in Ames mice that are genetically Pit-1 deficient (Sun et al., 2005a,b). Somatotrophs are, nevertheless the principle site of GH gene expression and the main source of the GH found in systemic circulation, since circulating GH concentrations are barely detectable following hypophysectomy or pituitary ablation. Pituitary GH is thus largely responsible for the endocrine actions of GH during perinatal and postnatal growth. The GH concentration in the pituitary gland is thus far higher than that in any extrapituitary location, but as the pituitary gland is much smaller than many extrapituitary tissues, the total amount of GH produced outside the pituitary gland is likely to be greater than that produced within it (Hull et al., 2005). In most cases the extrapituitary GH produced is thought to act in local autocrine or paracrine regulation, rather than to contribute to the pool of GH in peripheral circulation, although mammary GH increases circulating GH concentrations in dogs to levels that can induce acromegaly (Eigenmann, 1984; Mol et al., 1999). 3. Pituitary GH expression: ontogeny Somatotrophs are present in all vertebrates prenatally, but species differ in the embryonic or fetal age at which they appear. For instance, somatotrophs are present in the human pituitary by the end of the first trimester of gestation (Baker and Jaffe, 1975; Bugnon et al., 1976) (by 0.33 gestation), whereas they are not present in the pituitary glands of rats (Setalo and Nakane, 1976; Khorram et al., 1983; 0.78 gestation), and mice (Gross and Longer, 1979; Wilson and Wyatt, 1993; 0.84 gestation) until the last trimester. Their ontogenic appearance in cows is at 0.29 of gestation (Dubois, 1971), in sheep at 0.34 gestation (Stokes and Boda, 1968), in pigs at 0.41 gestation (Danchin and Dubois, 1982; Dacheux, 1984) and in chickens at 0.57 of incubation (Porter et al., 1995). Fetal or embryonic growth prior to the appearance of pituitary somatotrophs therefore occurs in the absence of pituitary GH and its secretion into systemic circulation (Harvey et al., 1998, 2000b). Organogenesis therefore occurs long before the ontogenic differentiation of Rathke’s pouch into the pituitary gland (Murphy and Harvey, 2001). Indeed, in chick embryos, 38 of the 46 identified Hamilton and Hamburger stages of morphogenesis (Hamburger and Hamilton, 1951; Davis and Garrison, 1968) occur before embryonic day 12 (ED12), the day on which somatotrophs are thought to be functionally present in the pituitary gland (Porter et al., 1995, 2001). Circulating GH is, however, not present in the plasma of chick embryos until ED17 (Harvey et al., 1979), or not until Hamburger and Hamilton stage 43, when embryogenesis is almost complete. 4. Extrapituitary GH expression Whereas pituitary GH expression does not occur in early embryonic or fetal development, extrapituitary GH is expressed much earlier and prior to organogenesis. GH mRNA is, for instance, found in rainbow trout zygotes within days of fertilization (Yang et al., 1999), with the commencement of embryonic genome transcription activity (EGTA) (Li et al., 2006, 2007). Similarly, the expression of GH mRNA can be detected in the larvae of the orange-spotted grouper within 1 day of hatching (Li et al., 2005). GH mRNA and GH-immunoreactive proteins also found in zebrafish embryos within 12 h of fertilization and in sea bass embryos within 76 h (Besseau et al., 2013). GH mRNA and GH-immunoreactivity are similarly found in chick embryos within 2 days of the

onset of incubation, before the appearance of discernible organ structures (Harvey, 2013). In the chick embryo, the expression of the GH gene appears to be almost ubiquitous and in every cell at ED4 (Harvey, 2013). GH-immunoreactivity is similarly widespread in early ED4 chick embryos, although by ED8 it is less abundant and more specific, being absent from some tissues and not present in every cell in those tissues that are GH-immunoreactive (Harvey et al., 2000b, 2001a). The presence of GH immunoreactivity in the ED5 chick is shown in (Fig. 1). GH appears to be abundantly and predominantly present in various nerve tracks of the spinal cord (Fig. 1A and C), including projecting axons innervating the limbs (Fig. 1A and D) and vertebral inclusions (Fig. 1A and E) in the spinal cord (Fig. 1A and C). GH was also detected in dorsal root ganglion (DRG) (Fig. 1A and B) and in bone in vertebral inclusions (Fig. 1A and E) and in the bone collar (Fig. 1C). The presence and presumptive role of GH in bone might be transient as GH immunoreactivity is no longer present there by ED7 (Murphy and Harvey, 2001) while it is detected in intercostal rib muscles at this later stage. Interestingly, GHR distribution mirrored that of GH, as it was detected in identical spinal tracts (Fig. 2), but also in DRG and bone. This suggests that GH and GHR might have an autocrine/paracrine role in these structures. Of interest, GH and GHR have been detected in projection neurons of the CNS, in particular in the visual system (Baudet et al., 2003, 2007; Harvey et al., 2007) where GH has been demonstrated to promote axon outgrowth and cell survival (Baudet et al., 2007; Harvey et al., 2006). It is thus possible that GH has broad autocrine/paracrine roles in projection neurons of the CNS.

5. Extrapituitary GH and embryonic growth Studies on the presence of extrapituitary GH have demonstrated its colocalization with GHR mRNA and/or GHR immunoreactivity in early embryos, within days of fertilization (e.g. in rainbow trout embryos, Li et al., 2007; in chick embryos, Harvey et al., 2000b; in mouse preimplantation embryos, Pantaleon et al., 1997). Similarly, GHR immunoreactivity in the ED chick embryo (Fig. 2) is clearly found in the same tissues that express GH immunoreactivity (Fig. 1). These findings suggest autocrine or paracrine actions of extrapituitary GH during early embryonic development. Indeed, the functional relevance of the GHRs in preimplantation mouse embryos was first shown by Pantaleon et al. (1997), by the demonstration that exogenous GH induced bellshaped dose response curves for 3-0-methyl glucose transport and for protein synthesis in these embryos. Exogenous GH was similarly found to regulate carbohydrate, lipid and energy metabolism in preimplantation bovine embryos, and to improve their ultrastructural features (Kolle et al., 2004). The possibility that these actions are receptor-mediated is supported by the fact that exogenous GH is able to increase the formation of both blastocysts and hatched blastocysts when incubated with two-cell-stage mouse embryos, especially as this action is blocked in the presence of specific GHR antibodies (Fukaya et al., 1998). The addition of exogenous GH to two-cell mouse preimplantation embryos was similarly shown to increase the number of cells in the trophectoderm (Markham and Kaye, 2003). These authors further showed that the proliferation of these cells in the mouse blastocyst is also suppressed by GHR antibodies. Interestingly, the immunoneutralization of endogenous GH did not affect the inner cell mass of these blastocysts, whereas the antibodies raised against insulin-like growth factor (IGF-)-1 did not affect the number of trophectoderm cells but did reduce the number of cells in the inner cell mass. The actions of GH are therefore not

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Fig. 1. Growth hormone (GH) immunoreactivity within a cross section of an ED5 chick embryo body. Methodology: whole embryos were fixed with Carnoy’s fixative, paraffin embedded and sectioned. Immunohistochemistry analysis was subsequently performed using rabbit anti-chicken GH (cGH-1) primary antibody (Baudet et al., 2003; dilution 1:1000 in 1% goat serum) dilution and the avidin biotin complex (ABC) method (Hsu et al., 1981). Staining was visualized using the chromogenic substrate diaminobenzidine tetrahydrochloride (DAB). (A) Low magnification photograph of GH immunoreactivity visualized in an ED5 chick embryo body. (B–E) High magnification images of: a vertebral condensation (arrow) and dorsal root ganglia (arrowhead) (B); spinal nerves (arrow) and bone collar (arrowhead) (C); spinal nerves innervating the limb (arrow) (D); spinal nerves (arrow) innervating a vertebral condensation (E). Abbreviations: a, anterior; d, dorsal; Me, Mesonephros; Nc, notochord; Sc, spinal cord; Ve, ventricle. Scale bars, (A) 1 mm; (B–E) lM.

mediated through IGF-1 and GH and IGF-1 are thought to act in concert to optimize blastocyst development. In addition to preimplantation embryos, extrapituitary GH expression in mammals has been demonstrated in the thymus and hematopoietic cells in the liver of the rat fetus at ED18 of the 21 days gestation period (Recher et al., 2001). GH transcripts were also observed in these animals in vascular endothelium and in the surrounding smooth muscle. Transcripts were also present in the myocardium of the left ventricle, in the kidney and in the intestine (Waters and Kaye, 2002). GH immunoreactivity is also present in the epithelium and mesenchyme of the primordial dental bud at ED17, prior to the onset of pituitary GH secretion at ED19 (Zhang et al., 1997). GH immunoreactivity is also present in the fetal rat brain before the onset of pituitary GH secretion (Hojvat et al., 1982). The functional importance of GH in the development of the early mammalian fetus was first shown by Nguyen et al. (1996) by the finding that the immunoneutralization of endogenous GH impaired the differentiation of the Wolffian duct in fetal rats, by a mechanism that was overcome by the administration of exogenous GH. The functional importance of extrapituitary GH in embryonic growth has also been demonstrated by Baudet et al. (2009) in ED7 chick embryos. These authors showed that exogenous GH increased the number and length of sprouting dendrites in cultured retinal ganglion cells (RGCs). They also found that the siRNA knockdown of RGC GH reduced the abundance and length of these

dendrites, demonstrating that their growth resulted from an autocrine or paracrine action of GH within the RGCs. The siRNA knockdown of GH in ED7 RGCs was also found to induce their apoptosis in vitro (Baudet et al., 2009; Sanders et al., 2010) and in vivo (Sanders et al., 2011), demonstrating an autocrine or paracrine role for retinal GH in RGC cell survival. This finding therefore supported earlier observations that showed that the immunoneutralization of endogenous GH in retinal cells (particularly RGCs) similarly resulted in cell death (Sanders et al., 2005, 2006, 2008, 2009a). In more recent studies, the immunoneutralization of endogenous GH in the cerebellum of embryonic chicks (Alba-Betancourt et al., 2011) was also found to promote cell survival through autocrine or paracrine mechanisms (Alba-Betancourt et al., 2013). The possibility that endogenous GH has functional activity in the chick embryo during embryogenesis is also supported by the fact that a GH-response gene (GHRG) is expressed in embryonic tissues. GHRH-1 is a specific marker of GH action in birds (Agarwal et al., 1995) and its is widely expressed in the chick embryo and colocalized (Harvey et al., 2001b), with GH and its receptor (Baudet et al., 2007). This suggests that endogenous GH is active in the embryo during embryonic growth. 6. Extrapituitary GH expression postnatally In addition to being expressed during early embryonic or fetal growth, extrapituitary GH gene expression persists in many tissues

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Fig. 2. Growth hormone receptor (GH) immunoreactivity within a cross section of an ED5 chick embryo body. Methodology: same as that described in Fig. 1 except that mouse anti-chicken GHR primary antibody (Baudet et al., 2007; dilution 1:1000 in 1% goat serum) was used instead. (A) Low magnification photograph of GHR immunoreactivity visualized in an ED5 chick embryo body. Abbreviations: arrow: spinal nerves: arrowhead: vertebral condensation. (B–E) High magnification images of: spinal nerves innervating the hindlimb (B); sensory nerve cell bodies in the dorsal root ganglia (C); spinal nerves innervating vertebral condensation (arrowhead) (D); spinal nerves (arrowhead) and cytoplasm of cells of a vertebral condensation (arrow) (E). Abbreviations: a, anterior; d, dorsal; Nc, notochord; Sc, spinal cord. Scale bars, (A) 1 mm, (B–E) 100 lM.

postnatally. It has, for instance, been found postnatally in the central and peripheral nervous systems, in the immune system (in the thymus, spleen, tonsils, lymph nodes, Peyers patches and Bursa of Fabricius), in reproductive tissues (the ovary, oviduct, uterus, mammary glands, placenta, testis and prostate), in gastrointestinal tissues (in hepatic tissues, pancreatic tissues, salivary tissues and the alimentary tract), in skeletal and dental tissue, in muscular tissues, in cardiovascular tissues (the heart and blood vessels), in respiratory tissues (in lungs and gills) and in integumentary tissues (skin) (reviewed in Harvey, 2010; Hrabia et al., 2013; Luna et al., 2013, in press; Rodriguez-Mendez et al., 2010). In the reproductive system, the persistence of extrapituitary GH postnatally likely reflects local autocrine or paracrine actions in gametogenesis and steroidogenesis (Hull and Harvey, 2000; Ahumada-Solorzano et al., 2012). The widespread expression of the GH gene in these sites may reflect a fundamental requirement of GH in cellular growth, differentiation, survival or metabolism (Sanders and Harvey, 2004, 2008). The widespread extrapituitary expression of the GH gene is therefore consistent with the almost ubiquitous expression of other factors involved in growth (e.g. the insulin-like growth factors (IGFs), parathyroid hormone related protein (PTHrP) and thyroid hormones) (Sanders and Harvey, 2008). While GH expression persists in some extrapituitary tissues postnatally, it is lost in others. For instance, GH immunoreactivity in the chick embryo disappears from the heart, liver and mesonephros by mid incubation (Harvey et al., 2000b). This presumably reflects an age-related extinction of GH expression in specific cells

and the subsequent onset of pituitary GH secretion and its acquisition of endocrine roles. As GHRs are found in all of the extrapituitary sites of GH gene expression, actions of GH in these sites may be endocrine and/or autocrine or paracrine and the mode of GH action may change during development. Local GH actions may thus, persists postnatally in those extrapituitary tissues that continue to express the GH gene. The postnatal expression of GH in the brain may therefore reflect continuing roles, for instance, in hippocampal function. This possibility is supported by the finding of high GH levels in the hippocampus of Ames mice (lacking pituitary GH expression), which was correlated with their higher rates of hippocampal neurogenesis (Sun et al., 2005a,b). The upregulation of the GH gene in the hippocampus following a learning paradigm (Donahue et al., 2002) also suggests its involvement in learning and memory. GH in the brain may also be involved in the regulation of rapid eye movement (REM) and non-REM sleep and in other behaviors and in electrocardiogram (EEG) activity (Obal et al., 1997). GH immunoneutralization in the rat brain also results in an increase in food intake (Zeinoaldini et al., 2006), suggesting the involvement of local GH in appetite regulation in postnatal animals. Within the postnatal brain, the overexpression of GH has also been found to regulate food intake, as a result of changes in the expression of orexigenic neuropeptides (Bohlooly et al., 2005; Olsson et al., 2005). The overexpression of GH in the cerebral cortex or hypothalamus of mice and rats has also been found to alter the expression of somatostatin and GH-releasing hormone (GHRH), resulting in alterations in pituitary GH secretion that result in

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dwarfism (Hollingshead et al., 1989; Flavell et al., 1996; Wells et al., 1997, 2003; Pellegrini et al., 1997). Local autocrine or paracrine actions of extrapituitary GH in the nervous system thus may have physiological significance in pituitary GH regulation. Within the postnatal brain, the expression of the GH gene is also likely to stimulate cell survival, as demonstrated in the chick embryo cerebellum (Alba-Betancourt et al., 2013). A lack of endogenous GH production in the RGCs of elderly humans with glaucoma has, conversely, been correlated with the RGC death that causes this debilitating visual disease (Sanders et al., 2009b). The increased RGC death that occurs in diabetic patients with retinopathy is similarly thought to be responsible for their lower vitreal GH concentrations (Harvey et al., 2009; Ziaei et al., 2009). In the periphery, GH gene expression persists postnatally in immune tissues (Weigent, 2013). However, this is not surprising, as GH is often considered as a cytokine (Waters et al., 1999) and its numerous immune actions (reviewed by Clark, 1997) are mediated through a receptor that is a member of Class 1 cytokine receptor superfamily. Being produced locally, immune GH is thus likely to be of functional significance, because its local production within immune cells allows GH to rapidly respond to an immune challenge (an emergency pathway) and to complement the slower (strategic) control of immune function regulated by its pituitary counterpart (Hull and Harvey, 1997). Its importance in postnatal immune function is illustrated by the reduced lymphocyte proliferation that occurs in the immune system of rats when immune GH expression is blocked by antisense oligonucleotides for GH mRNA (Weigent et al., 1991) and when immune GH is immunoneutralized by GH antibodies (Sabharwal and Varma, 1996; Segard et al., 2003). Treatment with a specific GHR antagonist to block the action of endogenous GH similarly demonstrates a functional autocrine or paracrine role of immune GH in cytokine production (Malarkey et al., 2002) and cell survival (Jeay et al., 2000). Endogenous GH in lymphocytes also appears to be functionally required for IGF-I production, since the number of IGF-I positive lymphocyte is reduced following GH immunoneutralization in vitro (Baxter et al., 1991). Tissue IGF-I concentrations are similarly reduced in the rat lung following the administration of an aerosolized antisense oligonucleotide directed against the GH gene (Beyea et al., 2009), suggesting a stimulatory autocrine or paracrine action of local lung GH on the lung proteome. In other peripheral tissues, the ability of mammary GH to promote the survival and proliferation of epithelial cells has been shown to be blocked in the presence of a specific GHR antagonist (Mukhina et al., 2004), suggesting this is normally induced by endogenous GH in an autocrine or paracrine way. 7. Summary Extrapituitary GH is of functional relevance in early embryonic or fetal growth and likely promotes tissue and whole-body growth in this growth-without-GH-syndrome. Blocking endogenous GH production (using GH antibodies, GH antisense oligonucleotides or GH siRNAs) or blocking GH action (using specific GHR antagonists) have also demonstrated functional roles for extrapituitary GH in perinatal or postnatal development. The continued extrapituitary production of GH postnatally therefore suggests continued autocrine or paracrine roles for local GH in some extrapituitary tissues. Local autocrine or paracrine actions of GH are, however, difficult to demonstrate postnatally, especially as the mere presence of GH mRNA or protein is not proof of functional significance. Functional responses demonstrated after the in vivo immunoneutralization of GH in postnatal animals (e.g. in bone, Loveridge et al., 1995; in skeletal muscle, Palmer et al., 1993; in the mammary gland, Flint


et al., 1992) may be confounded by the simultaneous removal of both pituitary and extrapituitary GH. Thus, while extrapituitary GH has functional relevance in early development in the absence of pituitary GH, its importance in most postnatal development is less certain when it occurs in the presence of pituitary GH. Acknowledgment Supported by NSERC (Natural Sciences and Research Council) (to S.H.) and the Giovanni Armenise-Harvard Foundation (to M.L.B.). References Agarwal, S.K., Cogburn, L.A., Burnside, J., 1995. Comparison of gene expression in normal and growth hormone-receptor dwarf chickens reveals a novel growth hormone regulated gene. Biochem. Biophys. Res. Commun. 206, 153–160. Ahumada-Solorzano, S.M., Carranza, M.E., Pedernera, E., Rodriguez-Mendez, A.J., Luna, M., Aramburo, C., 2012. Local expression and distribution of growth hormone and growth hormone receptor in the chicken ovary: effects of GH on steroidogenesis in cultured follicular granulosa. Gen. Comp. Endocrinol. 175, 297–310. Alba-Betancourt, C., Aramburo, C., Avila-Mendoza, J., Ahumada-Solozano, S.M., Carranza, M., Rodriguez-Mendez, A.J., Harvey, S., Luna, M., 2011. Expression, cellular distribution, and heterogeneity of growth hormone in the chicken cerebellum during development. Gen. Comp. Endocrinol. 170, 528–540. Alba-Betancourt, C., Luna-Acosta, J.L., Ramirez-Martinez, C.E., Avila-Bonzalez, D., Granados-Avalos, E., Carranza, M., Martinez-Coria, H., Aramburo, C., Luna, M., 2013. Neuro-protective effects of growth hormone (GH) after hypoxia–ischemia injury in embryonic chicken cerebellum. Gen. Comp. Endocrinol. 183, 17–31. Baker, B.L., Jaffe, R.B., 1975. The genesis of cell types in the adenohypophysis of the human fetus as observed with immunocytochemistry. Am. J. Anat. 143, 137– 161. Baudet, M.-L., Sanders, E.J., Harvey, S., 2003. Retinal growth hormone in the chick embryo. Endocrinology 144, 5459–5468. Baudet, M.-L., Rattray, D., Harvey, S., 2007. Growth hormone and its receptor in projection neurons of the chick visual system: retinofugal and tectobulbar tracts. Neuroscience 148, 151–163. Baudet, M.-L., Rattray, D., Martin, B.T., Harvey, S., 2009. Growth hormone promoters axon growth in the developing nervous system. Endocrinology 150, 2758–2766. Baxter, J.B., Blalock, J.E., Weigent, D.A., 1991. Characterization of immunoreactive insulin-like growth factor-I from leukocytes and its regulation by growth hormone. Endocrinology 129, 1727–1734. Besseau, L., Fuentes, M., Sauzet, S., Beauchaud, M., Chatain, B., Coves, D., Boeuf, G., Falcon, J., 2013. Somatotropic axis genes are expressed before pituitary onset during zebrafish and sea bass development. Gen. Comp. Endocrinol. 194C, 133– 141. Beyea, J., Olson, D.M., Harvey, S., 2009. Growth hormone-dependent changes in rat lung proteome during alveorization. Mol. Cell. Biochem. 321, 197–204. Bohlooly, Y.M., Olsson, B., Bruder, C.E., Linden, D., Sjorgren, K., Bjursell, M., Egecioglu, E., Svensson, L., Brodin, P., Waterton, J.C., Isakson, O.G., Sundle, F., Ahren, B., Ohlsson, C., Orcarsson, J., Tornell, F., 2005. Growth hormone expression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia. Diabetes 54, 51– 62. Bugnon, C., Lenys, D., Bloch, G.B., Fellman, D., 1976. Immunocytochemical study using semi-thin sections of the phenomena of early differentiation in several cell populations of the human fetal adenohypophysis. C.R. Seances Soc. Biol. Fil. 170, 975–982. Clark, R., 1997. The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocrine Res. 18, 157– 179. Dacheux, F., 1984. Differentiation of cells producing polypeptide hormones (ACTH, MSH, LPH, alpha- and beta-endorphin, GH and PRL) in the fetal porcine anterior pituitary. Cell Tissue Res. 235, 615–621. Danchin, E., Dubois, M.P., 1982. Immunocytological study of the chronology of pituitary cytogenesis in the domestic pig. Reprod. Nutr. Dev. 22, 135–151. Davis Jr., J.E., Garrison, N.E., 1968. Mean weights of chick embryos correlated with the stages of Hamburger and Hamilton. J. Morphol. 124, 79–82. Deayton, J.M., Young, I.R., Thorburn, G.D., 1993. Early hypophysectomy of sheep fetuses: effects on growth, placental steroidogenesis and prostaglandin production. J. Reprod. Fertil. 97, 513–520. Donahue, C.P., Jensen, R.V., Ochiishi, T., Eisenstein, I., Zhao, M., Shors, T., Kosik, K.S., 2002. Transcriptional profiling reveals regulated genes in the hippocampus during memory formation. Hippocampus 12, 821–833. Dubois, M.P., 1971. Appearance of hormonal secretions in the bovine fetal pituitary gland: immunofluorescence demonstration of gonadotropic cells and thyrotropic cells. C.R. Acad. Sci. Hebd. Seances Acad. Sci. D. 272, 1793–1795. Eigenmann, J.E., 1984. Acromegaly in the dog. Vet. Clin. North Am. Small Anim. Pract. 14, 827–836.

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Extrapituitary growth hormone and growth?

While growth hormone (GH) is obligatory for postnatal growth, it is not required for a number of growth-without-GH syndromes, such as early embryonic ...
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