Comprehensive Physiology Wiley Online Library

Development of the Pituitary Gland

Full Article on Wiley Online Library



Abstract

The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme. Endocrine cells of the pituitary gland are organized into structural and functional networks that contribute to the coordinated response of endocrine cells to stimuli; these cellular networks are formed during embryonic development and are maintained or may be modified in adulthood, contributing to the plasticity of the gland. Abnormalities in any of the steps of pituitary development may lead to congenital hypopituitarism that includes a spectrum of disorders from isolated to combined hormone deficiencies including syndromic disorders such as septo‐optic dysplasia. Over the past decade, the acceleration of next‐generation sequencing has allowed for rapid analysis of the patient genome to identify novel mutations and novel candidate genes associated with hypothalmo‐pituitary development. Subsequent functional analysis using patient fibroblast cells, and the generation of stem cells derived from patient cells, is fast replacing the need for animal models while providing a more physiologically relevant characterization of novel mutations. Furthermore, CRISPR‐Cas9 as the method for gene editing is replacing previous laborious and time‐consuming gene editing methods that were commonly used, thus yielding knockout cell lines in a fraction of the time. © 2020 American Physiological Society. Compr Physiol 10:389‐413, 2020.

Keywords: pituitary; endocrinology and metabolism; anterior pituitary; neurophysiology

Figure 1. Figure 1. Schematic presentation of the stages of pituitary development in rodents: (A) Oral ectoderm; (B) Rudimentary pouch; (C) Definitive pouch; (D) Adult pituitary gland. The close contact between the developing Rathke's pouch (red) and the infundibulum (yellow) is maintained throughout and is important for the normal morphogenesis of the gland. I, Infundibulum; NP, neural plate; N, notochord; PP, pituitary placode; OM, oral membrane; H, heart; F, forebrain; MB, midbrain; HB, hindbrain; RP, Rathke's pouch; AN, anterior neural pore; O, oral cavity; PL, posterior lobe; OC, optic chiasm; P, pontine flexure; PO, pons; IL, intermediate lobe; AL, anterior lobe; DI, diencephalon; SC, sphenoid cartilage. Reused, with permission, from Kelberman D, et al., 2009 114.
Figure 2. Figure 2. Pituitary organogenesis during human embryonic development. (A) Midline sagittal hematoxylin and eosin‐stained section of a Carnegie stage (CS) 13 embryo, at approximately 5 weeks of development, showing the invagination of the oral ectoderm to form Rathke's pouch (arrow). (B) Sagittal section of CS14 embryo showing the developing Rathke's pouch coming into contact with the overlying neuroectoderm. (C) Sagittal section of CS15 embryo showing the definitive Rathke's pouch becoming separated from the oral ectoderm. Panel (D) at CS 17, the definitive Rathke's pouch is fully separated from the oral ectoderm and maintains contact with the neural ectoderm of the diencephalon. Rp, Rathke's pouch; oe, oral ectoderm; Di, diencephalon. Scale bars: (A) and (D), 300 μm; (B) and (C), 100 μm. Reused, with permission, from Kelberman D, et al., 2009 114.
Figure 3. Figure 3. Schematic cascade of transcription factors and signaling molecules during pituitary development. The terminal differentiation of the anterior pituitary cell types is the result of complex interactions between extrinsic signaling molecules and transcription factors (HESX1, SOX2, SOX3, OTX2, LHX3, LHX4, GATA2, ISL1, PROP1, and POU1F1). Mutations in the early developmental transcription factors result in pituitary hormone deficiencies in association with structural pituitary abnormalities and/or extrapituitary defects (i.e., ocular or skeletal abnormalities, midline and other central nervous system defects, sensorineural deafness, and developmental delay). Mutations in the later transcription factors result in combined or isolated pituitary hormone deficiencies, depending on the factor affected. Reused, with permission, from Kelberman D, et al., 2009 114.
Figure 4. Figure 4. Sox2 expression and abnormal morphogenesis of the pituitary gland in Sox2 heterozygote mice. (A) Sagittal section of an 11.5‐dpc wild‐type embryo hybridized to Sox2, shows expression in both the CNS and Rathke's pouch. (B,C) Sagittal sections of 12.5‐dpc wild‐type (B) and Sox2 heterozygous (C) embryos demonstrate bifurcation of the pouch in the mutant embryo. (D,E) Pituitary transverse sections of 5‐week‐old wild‐type (D) and Sox2 heterozygous mice (E). There is presence of an extra cleft in the Sox2 heterozygous pituitary (arrow). The bifurcated Rathke's pouch is reminiscent of the abnormal shape in mouse mutants with disruption of Hesx1 63, Sox3, Wnt5a 39, or Shh 241. HYP, Presumptive hypothalamus; RP, Rathke's pouch. Scale bars: 0.1 mm. Reused, with permission, from Kelberman D, et al., 2006 113.
Figure 5. Figure 5. Pituitary MRI of patients with congenital hypopituitarism (B–F) compared to normal MRI appearance (A). (A) Midsagittal MRI scan of a normal child, showing a well‐formed corpus callosum (CC), normal optic chiasm (OC), and the posterior pituitary (PP), which appears as a bright spot within the sella turcica. (B) Sagittal MRI scan of two siblings with a homozygous p.R160C mutation in HESX1. In the first sibling (i), the splenium of the corpus callosum is more hypoplastic than the rest of the structure, and the posterior pituitary is partially descended as compared with the other sibling (ii) who has a severely hypoplastic corpus callosum, ectopic posterior pituitary, and lack of visible pituitary stalk (PS). (C) Coronal and sagittal MRI scans from one patient [panels (i) and (ii)] and sagittal scan from a second patient (iii) with SOX3 duplication showing anterior pituitary (AP) hypoplasia, partial hypoplasia of the infundibulum (I) in the first patient and complete absence in the second, and an ectopic posterior pituitary which is more severe in the second patient. (D) MRI scans from patient with SOX2 mutations. Sagittal section from patient with c60insG mutation showing anterior pituitary (ap) hypoplasia with normal posterior pituitary (pp) and infundibulum (i) and a hypothalamic hamartoma (h). (E) Sagittal MRI scan in patient with compound heterozygosity for p.E230K and p.R172Q mutations in POU1F1, showing hypoplasia of the anterior pituitary gland with a normal posterior pituitary and infundibulum. (F) Sequential MRI scanning of a patient with a 13‐bp deletion (c.112_124del13) in PROP1 reveals waxing and waning of a pituitary mass (arrow): (i) on initial presentation, (ii) after 4 months, (iii) after 12 months, and (iv) 21 months after initial MRI. Reused, with permission, from Kelberman D, et al., 2009 114.


Figure 1. Schematic presentation of the stages of pituitary development in rodents: (A) Oral ectoderm; (B) Rudimentary pouch; (C) Definitive pouch; (D) Adult pituitary gland. The close contact between the developing Rathke's pouch (red) and the infundibulum (yellow) is maintained throughout and is important for the normal morphogenesis of the gland. I, Infundibulum; NP, neural plate; N, notochord; PP, pituitary placode; OM, oral membrane; H, heart; F, forebrain; MB, midbrain; HB, hindbrain; RP, Rathke's pouch; AN, anterior neural pore; O, oral cavity; PL, posterior lobe; OC, optic chiasm; P, pontine flexure; PO, pons; IL, intermediate lobe; AL, anterior lobe; DI, diencephalon; SC, sphenoid cartilage. Reused, with permission, from Kelberman D, et al., 2009 114.


Figure 2. Pituitary organogenesis during human embryonic development. (A) Midline sagittal hematoxylin and eosin‐stained section of a Carnegie stage (CS) 13 embryo, at approximately 5 weeks of development, showing the invagination of the oral ectoderm to form Rathke's pouch (arrow). (B) Sagittal section of CS14 embryo showing the developing Rathke's pouch coming into contact with the overlying neuroectoderm. (C) Sagittal section of CS15 embryo showing the definitive Rathke's pouch becoming separated from the oral ectoderm. Panel (D) at CS 17, the definitive Rathke's pouch is fully separated from the oral ectoderm and maintains contact with the neural ectoderm of the diencephalon. Rp, Rathke's pouch; oe, oral ectoderm; Di, diencephalon. Scale bars: (A) and (D), 300 μm; (B) and (C), 100 μm. Reused, with permission, from Kelberman D, et al., 2009 114.


Figure 3. Schematic cascade of transcription factors and signaling molecules during pituitary development. The terminal differentiation of the anterior pituitary cell types is the result of complex interactions between extrinsic signaling molecules and transcription factors (HESX1, SOX2, SOX3, OTX2, LHX3, LHX4, GATA2, ISL1, PROP1, and POU1F1). Mutations in the early developmental transcription factors result in pituitary hormone deficiencies in association with structural pituitary abnormalities and/or extrapituitary defects (i.e., ocular or skeletal abnormalities, midline and other central nervous system defects, sensorineural deafness, and developmental delay). Mutations in the later transcription factors result in combined or isolated pituitary hormone deficiencies, depending on the factor affected. Reused, with permission, from Kelberman D, et al., 2009 114.


Figure 4. Sox2 expression and abnormal morphogenesis of the pituitary gland in Sox2 heterozygote mice. (A) Sagittal section of an 11.5‐dpc wild‐type embryo hybridized to Sox2, shows expression in both the CNS and Rathke's pouch. (B,C) Sagittal sections of 12.5‐dpc wild‐type (B) and Sox2 heterozygous (C) embryos demonstrate bifurcation of the pouch in the mutant embryo. (D,E) Pituitary transverse sections of 5‐week‐old wild‐type (D) and Sox2 heterozygous mice (E). There is presence of an extra cleft in the Sox2 heterozygous pituitary (arrow). The bifurcated Rathke's pouch is reminiscent of the abnormal shape in mouse mutants with disruption of Hesx1 63, Sox3, Wnt5a 39, or Shh 241. HYP, Presumptive hypothalamus; RP, Rathke's pouch. Scale bars: 0.1 mm. Reused, with permission, from Kelberman D, et al., 2006 113.


Figure 5. Pituitary MRI of patients with congenital hypopituitarism (B–F) compared to normal MRI appearance (A). (A) Midsagittal MRI scan of a normal child, showing a well‐formed corpus callosum (CC), normal optic chiasm (OC), and the posterior pituitary (PP), which appears as a bright spot within the sella turcica. (B) Sagittal MRI scan of two siblings with a homozygous p.R160C mutation in HESX1. In the first sibling (i), the splenium of the corpus callosum is more hypoplastic than the rest of the structure, and the posterior pituitary is partially descended as compared with the other sibling (ii) who has a severely hypoplastic corpus callosum, ectopic posterior pituitary, and lack of visible pituitary stalk (PS). (C) Coronal and sagittal MRI scans from one patient [panels (i) and (ii)] and sagittal scan from a second patient (iii) with SOX3 duplication showing anterior pituitary (AP) hypoplasia, partial hypoplasia of the infundibulum (I) in the first patient and complete absence in the second, and an ectopic posterior pituitary which is more severe in the second patient. (D) MRI scans from patient with SOX2 mutations. Sagittal section from patient with c60insG mutation showing anterior pituitary (ap) hypoplasia with normal posterior pituitary (pp) and infundibulum (i) and a hypothalamic hamartoma (h). (E) Sagittal MRI scan in patient with compound heterozygosity for p.E230K and p.R172Q mutations in POU1F1, showing hypoplasia of the anterior pituitary gland with a normal posterior pituitary and infundibulum. (F) Sequential MRI scanning of a patient with a 13‐bp deletion (c.112_124del13) in PROP1 reveals waxing and waning of a pituitary mass (arrow): (i) on initial presentation, (ii) after 4 months, (iii) after 12 months, and (iv) 21 months after initial MRI. Reused, with permission, from Kelberman D, et al., 2009 114.
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Kyriaki S. Alatzoglou, Louise C. Gregory, Mehul T. Dattani. Development of the Pituitary Gland. Compr Physiol 2020, 10: 389-413. doi: 10.1002/cphy.c150043