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Department of Neurobiology and Physiology and The Center for Reproductive Science Northwestern University Evanston, Illinois 60208
Address all correspondence and requests for reprints to: Jon E. Levine, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: jlevine{at}northwestern.edu.
Vertebrate reproduction is completely dependent upon the neurosecretion of the decapeptide GnRH (major mammalian form GnRH-1), from a mere 700-2000 neurosecretory cells in the basal forebrain (1, 2). The pulsatile release of the decapeptide directs the synthesis and secretion of the gonadotropins, LH and FSH, and in its absence gonadotropin secretions cease, steroidogenesis and gametogenesis in the gonads of both sexes are compromised, and infertility results (3). It is no surprise, then, that congenital abnormalities that lead to improper development and function of GnRH-1 neurons produce a failure of puberty and hypogonadotropic hypogonadal infertility. An understanding of the molecular and cellular mechanisms mediating normal and abnormal GnRH neuronal development has thus remained a vital objective among reproductive neuroendocrinologists.
Thanks to a little fish, the medaka Oryzias latipes, and the elegant work of Okubo et al. (4) described in this issue, the embryonic origins of GnRH neurons have just become better understood—and found to be even more peculiar and interesting than previously thought. The basic ontogeny of GnRH-1 neurons was first described in 1989 by the laboratories of Susan Wray (5) and Donald Pfaff (6), who independently demonstrated that the populations of GnRH neurons that regulate the reproductive axis originate in embryonic olfactory tissues. Their immunohistological studies convincingly showed that GnRH neurons are located in the olfactory placode in the early stages of embryogenesis, and that the disappearance of these neurons from the olfactory pit and nasal septum over successive days is correlated with the appearance of GnRH-1 neurons along the terminal nerve and within the central nervous system. Many histological and tissue culture studies (e.g. Refs.7 and 8) have since confirmed the conclusion made obvious by these initial studies. During prenatal development, these neurons undergo a remarkable axophilic migration from the medial olfactory placodal region, across the terminal nerve to their ultimate locations along a septo-preoptic-hypothalamic continuum in the basal forebrain. Thereafter, they extend axonal processes into the median eminence and establish neurovascular connections through which they regulate the reproductive axis.
End of story? Not by a long shot. The trek of the neuroendocrine GnRH-1 neuronal population, from the periphery into the developing brain, remains a fascinating developmental phenomenon, and much work continues toward identifying the cellular elements and molecular cues that guide this process. The roles that any such factors, including extracellular matrix proteins, neurotransmitters, and transcription factors, may play in human syndromes of hypogonadotropic hypogonadism also remain a pressing issue. The basic story of the migrating GnRH neuron, however, has remained a virtually immutable certainty, despite the fact that this dynamic process has not actually been observed in vivo, and in real time—until now. Okubo et al. (4) have developed transgenic medaka models that specifically express green fluorescent protein (GFP) in their GnRH neurons, as has been done in mice (9, 10) and rats (11). However, because these animals exhibit optical clarity during embryogenesis, the GFP-expressing GnRH neurons in the transgenic medaka can be visualized externally, thereby allowing the monitoring of GnRH neuronal migratory patterns in vivo.
The study provides stunning results that are all at once expected, unexpected, and guaranteed to open doors for future study. This includes the clear demonstration that a GnRH neuronal population controlling pituitary function does indeed migrate from the developing olfactory compartment. This population assumes a final location in the ventral preoptic area, extends processes to the anterior pituitary, and is likely analogous to the hypophysiotropic GnRH neuronal population described in mammals. This result would be expected for mammalian species, but less so for nonmammalian vertebrates, where hypophysiotropic GnRH neurons have been thought to have a different embryonic origin (12). The present study thus firmly establishes that the ventral preoptic GnRH neurons have a conserved embryological origin.
The medaka model also provides some relative surprises about the multiplicity of GnRH neuronal groups and their embryonic origins. Apart from the ventral preoptic GnRH-1 neuronal group, the present work also identifies a dorsal preoptic GnRH-1 cell population that migrates from the dorsal telencephalon, a medial ventral telencephalic GnRH-1 cell population that migrates from the anterior telencephalic area, and a nonmigratory ventral hypothalamic GnRH-1 cell population. These three neuronal populations do not appear to project to the anterior pituitary, and thus their functions remain to be elucidated. Whether or not they correspond to specific GnRH neuronal populations in mammalian species also emerges as an important question.
The GnRH-1 cell populations are largely nonoverlapping with neuronal populations that express the other two paralogous GnRH genes in fish, GnRH-2 and GnRH-3. It has been demonstrated in medaka (13) and other fish species (14) that the forebrain cell groups express either GnRH-1 or GnRH-3, with the preoptic GnRH-1 neuronal population regulating gonadotropin secretion, and a terminal nerve GnRH-3 neuronal population likely playing a role in the regulating reproductive behaviors (15). In their present work, Okubo et al. (4) also generated a second transgenic medaka expressing GFP in GnRH-3 neurons, and thereby determined that the terminal nerve GnRH-3 cell group is of olfactory origin. Some intriguing new findings also emerged from the study of these embryos: a GnRH-3 expressing cell group resides in the trigeminal ganglion, and maternal GnRH-3 expression occurs in oocytes and early embryos—functions to be determined.
The transgenic medaka model bestows an additional gift to the clinical neuroendocrine research community. The underlying molecular and genetic defects that produce certain types of hypogonadotropic hypogonadism, such as Kallmann’s syndrome, may also be directly analyzed using the transgenic medaka model, as demonstrated by Okubo et al. (4). The association of hypogonadotropic hypogonadism and anosmia is known as Kallmann’s syndrome, with both autosomal and X-linked patterns of inheritance being recorded (16, 17, 18). Kallmann’s syndrome appears to result from failure of the GnRH neurons to migrate to the hypothalamus (19). Genetic mutations in X-linked Kallmann’s syndrome affect the KAL gene on the X chromosome, which encodes an adhesion protein called anosmin, a protein that appears to be indispensable for the GnRH-1 cell migration to proceed normally (20, 21, 22). The pathogenesis of X-linked Kallmann’s has been difficult to study, however, because the mouse and rat homologs for the KAL gene have not been identified. In this regard, the medaka has again proved to be most accommodating; Okubo et al. have identified two medaka homologs of the human KAL1 gene, kal1.1 and kal1.2, and demonstrate that the knockdown of kal1.1 expression disrupted GnRH-1 neuronal migration into the forebrain, essentially recapitulating the histological features of X-linked Kallmann’s syndrome.
The work of Okubo et al. has clearly revealed the transgenic medaka as the little fish that will keep on giving, at least to grateful neuroendocrinologists and developmental neurobiologists. These studies also reinforce the value of a comparative approach to address the molecular and cellular basis of human disease, and suggest that sometimes it really can be a good thing to go on a fishing expedition.
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Abbreviation: GFP, Green fluorescent protein.
Received December 15, 2005.
Accepted for publication December 19, 2005.
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