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BOR - Papers in Press, published online ahead of print July 30, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.028555
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BIOLOGY OF REPRODUCTION 71, 1822–1827 (2004)
DOI: 10.1095/biolreprod.104.028555
© 2004 by the Society for the Study of Reproduction, Inc.

Embryo

Primordial Germ Cell Migration in the Rat: Preliminary Evidence for a Role of Galactosyltransferase1

Soma Bandyopadhyay3, Sutapa Banerjee3, Alok K. Pal3, Sourendra K. Goswami4, Baidyanath Chakravarty4, and Syed N. Kabir2,3

Reproductive Biology Research,3 Indian Institute of Chemical Biology, Jadavpur, Kolkata 700032, West Bengal, India Institute of Reproductive Medicine,4 Salt Lake, Kolkata 700091, West Bengal, India


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The precise cellular mechanism of primordial germ cell (PGC) migration remains unknown. Cell surface galactosyltransferase (GalTase) is known to play unique roles in the process of locomotion of many migratory cells. With an objective to seek evidence for possible involvement of GalTase in the migratory process of PGC, we evaluated germ cell migration in the rat following experimental modulation of embryonic GalTase activity. Pregnant rats were laparotomized under anesthesia on Day 10 of pregnancy. While embryos of one uterine horn received lysozyme (100 µg/fetus), those of the other received {alpha}-lactalbumin (LA; 100 µg/fetus), N-acetylglucosamine (GlcNAc; 250 nmole/fetus), uridine 5'-monophosphate (UMP; 2.5 µmole/fetus), uridine diphosphate-galactose (UDP-gal; 250 nmole/fetus), or a combination of 250 nmole of UDP-gal and 2.5 µmole of UMP/fetus. Between gestation Days 12 and 14, embryos were dissected out and processed for histochemical localization of PGC on the basis of binding of Dolichos biflorus agglutinin on the surface glycoconjugate of the germ cells. The number of PGC in each embryo was counted. There was a daywise increase in the number of PGC in all groups. As compared with lysozyme-exposed controls, the numbers of PGCs at the day-specific sites on all days of examination were significantly lower in the LA- as well as GlcNAc-exposed groups. UMP or UDP-gal individually exerted little or no influence, while the total PGC count rose significantly over the respective control values under simultaneous exposure to UMP and UDP-gal. The present findings suggest a likely catalytic role of GalTase in the process of germ cell migration.

developmental biology, early development, embryo, galactosemia, galactosyltransferase, germ cell migration, N-acetylglucosamine, ovary, oocyte development, premature ovarian failure


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The origin, migration, and proliferation of primordial germ cells during embryogenesis hold the key for successful establishment of normal reproductive functions. In vertebrates, the primordial germ cell (PGC) precursors are thought to originate in the epiblast [1]. They form part of the extraembryonic mesoderm and gradually migrate to the genital ridge to populate the gonad [2, 3]. There is little insight into the precise cellular mechanisms involved in the guidance of germ cells to the gonadal ridge; however, some chemotaxis is clearly operational. Previous workers have demonstrated the localization of a number of glycoconjugates on the surface of PGCs of some animals [4–6]. Fazel et al. [7] reported that a unique glycoconjugate with terminal N-acetylgalactosamine (GalNAc) is selectively and transiently expressed on the PGC during the course of active migration in the rat. The precise roles of these glycans are uncertain, but their possible implications in the process of PGC migration have been envisioned. Complementary molecules like glycoconjugates and enzymes have long been known to play important roles in cell adhesion and migration mechanisms [6, 8, 9]. Migrating embryonic cells are known to possess high levels of cell-surface galactosyltransferase (GalTase) that functions as a recognition molecule in many cellular interactions, including their locomotion [10, 11]. A novel enzymatic mechanism involving GalTase-mediated transfer of galactose from UDP-galactose (UDP-gal) at the cell surface to the terminal N-acetylglucosamine (GlcNAc) residues on glycoconjugates within the extracellular matrix (ECM) has been implicated in the translocation of neural crest cells [12]. Although no knowledge exists of the presence of UDP-gal in the extracellular milieu or on the surface of the PGC, there are propositions that the same mechanism may be operative in the locomotive movements of PGC [7]. Consistent with this are the findings that GalTase is localized on the PGC surface [13], and in the mouse, as the PGCs leave the dorsal mesentery, they get accumulated on a ribbon of laminin [6]—a principal GalTase substrate in the basal lamina.

The hypothesized role of GalTase in the process of oogonial migration has also been supported by some indirect but discrete observations. Premature ovarian failure (POF) is a frequent finding in women with galactosemia [14–16]. We have recently demonstrated that experimental galactose toxicity in the rat, a condition characterized by deficiency of UDP-gal with accumulation of galactose and galactose-1-phosphate (gal-1-P) [17] that attenuate GalTase activity [18], perturbed PGC migration and resulted in the development of ovaries with deficient initial pools of oogonia [19]. Therefore, deficiency of UDP-gal and/or GalTase may represent the missing link between galactosemia and POF, while inhibited germ cell migration under such a deficient state further attests to the possible involvement of a UDP-gal-GalTase mechanism in the migratory process. The present investigation explores germ cell migration in rats under the modulatory influence of some GalTase modifier agents to authenticate the hypothetical enzymatic mechanism of germ cell migration.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals

The following materials were commercially available: {alpha}-lactalbumin (LA), lysozyme, GlcNAc, uridine 5'-monophosphate (UMP), UDP-gal, glutaraldehyde, mercuric chloride, sodium acetate, Lugol solution, Dolichos biflorus agglutinin (DBA)-horseradish peroxidase (HRP) conjugate, diaminobenzidine (DAB)-peroxidase substrate, and Alcian blue (Sigma Chemical Co., St. Louis, MO).

Animals

The experiments were performed in accordance with the guidelines formulated by the Committee for the Purpose of Control and Supervision of Experiments on Animals, Ministry of Culture, India, with approval from the Animal Ethics Committee of Indian Institute of Chemical Biology. Sprague-Dawley rats, procured from the random bred colony of the animal house of our institute, were maintained under good husbandry conditions supported by diurnal cycles of 12L:12D with lights on at 0600 h daily. They were given access to standard pelleted food and filtered tap water ad libitum. Adult female rats were mated with proven fertile males of the same strain, and the presence of sperm in the vaginal lavage was assigned as Day 1 of gestation. The pregnant rats (n = 88) were allocated into five groups. On gestation Day 10 at 1200 h (±15 min), laparotomy was performed under light ether anesthesia and the uterine horns were carefully pulled out. The fetuses of the left uterine horn were injected with LA (100 µg/fetus) (n = 20), GlcNAc (250 nmole/fetus) (n = 16), UMP (2.5 µmole/ fetus) (n = 16), UDP-gal (250 nmole/fetus) (n = 18), or a combination of 250 nmole of UDP-gal and 2.5 µmole of UMP/fetus (n = 18), while those of the contralateral horns were injected with lysozyme (100 µg/ fetus). Each test material was injected in a 3-µl volume dispensed through a 30-gauge needle fitted with a Hamilton syringe and penetrated through the antimesometrial surface of the implantation sites. Care was taken to prevent any entry of air bubbles or leakage during injection. Then the uterus was placed back gently into the peritoneal cavity. The muscle layer was closed by sutures and the skin was closed with the help of wound clips. The animals were maintained under proper postoperative care until gestation Days 12–14, when 5–8 rats from each group were killed at 1600 h (±15 min) by cervical dislocation. The uterine horns were removed and dissected in PBS. Fetuses from each uterine horn were separated from deciduas and extraembryonic membranes and processed separately for histochemical localization of PGCs.

Fixation and Processing of Embryos

Fixation of the embryos was carried out in a solution of 6% mercuric chloride, 1% sodium acetate, and 0.1% glutaraldehyde [20] for 18 h at room temperature. The embryos were then dehydrated through graded alcohols and xylene and embedded in paraffin blocks.

Histochemical Localization of Germ Cells

The PGCs were histochemically stained by the method described by Fazel et al. [7]. Serial sagittal sections cut at 5 µm thickness were deparaffinized and rehydrated through descending grades of ethanol. The sections were then treated with Lugol solution to remove mercuric salts. After washing in 0.1 M PBS, pH 7.2, the sections were flooded with a solution containing 10–20 µg/ml DBA-HRP conjugate in 0.1 M PBS, pH 7.2, containing 0.1 mM CaCl2, MnCl2, and MgCl2 for 2 h at 4°C. Following thorough rinsing in PBS, the sections were incubated in a DAB-peroxidase substrate medium (pH 7.0) for 15 min at room temperature [21]. Finally, the sections were counterstained with 1% solution of Alcian blue in 3% acetic acid (pH 2.5).

Quantification of Germ Cells

The numbers of germ cells in each embryo were estimated by the method as originally described by Abercrombie [22] for quantification of nuclei population in microtome sections. The average diameter of ~100 PGC in each group and on each day of examination was measured by an ocular micrometer at 400x magnification and calibrated with an object micrometer on the microscope plate. The total numbers of sections covering the region of expected localization of PGC on the specific days were noted. DBA-reactive cells were counted in 16–20 embryos on each day of examination with 15–20 sections per embryo. Three persons, including one who was not associated with the study, did all counting blindly. The average number of PGC in a section (P) was derived by the equation P = A x M/(L + M), where A is the crude number of PGCs seen in the section, M is the thickness (in µm) of the section, and L is the average diameter of PGC (in µm). The total number of PGCs in each embryo (N) was derived by the equation N = P x n, where n is the number of sections obtained through the site of localization of PGC in individual embryos.

Statistics

The data were expressed as mean ± SD. Differences in germ cell numbers within and between groups were analyzed by one-way ANOVA.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Figure 1 illustrates the distribution of PGC on the migratory path during their active course of migration under controlled and GalTase-attenuated states. PGC were distinctly differentiated from all other cells by their relatively larger size, low abundance, and, above all, their intense DBA reactivity. In the lysozyme-exposed Day-12 embryos, PGCs were found lying in the epithelium and scattered posterior to the developing hindgut (Fig. 1, A1). In Day-13 embryos (Fig. 1, A2), they were distributed along the coelomic epithelium covering the dorsal mesentery. The cells were primarily aligned in contact with the epithelium's basement membrane, while some cells had apparently invaded the epithelium. By Day 14, the PGCs increased significantly in numbers over their earlier population and were located in the epithelium and mesenchyme of the genital ridge (Fig. 1, A3). In all study groups, the presence of PGC was documented at the day-specific locations on each day of examination with an identical distribution pattern; however, they differed in respect to their population density. As compared with those of the respective lysozyme controls (Fig. 1, A1–A3), the PGC populations were significantly sparser in both LA- (Fig. 1, B1–B3) and GlcNAc-exposed embryos (Fig. 1, C1–C3). The PGC colonies in the UMP- (Fig. 1, D1–D3) and UDP-gal-treated (Fig. 1, E1–E3) embryos were almost comparable with those of the day-specific lysozyme controls (Fig. 1, A1–A3). The embryos exposed simultaneously to UMP and UDP-gal (Fig. 1, F1– F3), however, demonstrated comparatively dense populations of PGC, which was more pronounced on Day 13 (Fig. 1, F2) and Day 14 (Fig. 1, F3).



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  		FIG. 1. Photomicrographs (A–F) show DBA-reactive PGC (arrows) on their path of migration in 12- to 14-day-old rat embryos exposed in utero to lysozyme (A1–A3), LA (B1–B3), GlcNAc (C1–C3), UMP (D1–D3), UDP-galactose (E1–E3), and UMP+UDP-galactose (F1–F3). PGCs are found scattered posterior to the developing hindgut in Day-12 embryos (A1, B1, C1, D1, E1, F1). Panels A2, B2, C2, D2, E2, F2 exhibit the distribution of PGC along the coelomic epithelium of the dorsal mesentery in 13-day old embryos. In 14-day-old embryos, PGCs are located in the epithelium and mesenchyme of the developing gonad (A3, B3, C3, D3, E3, F3). The daywise distribution patterns of PGC in all study groups are qualitatively akin to those of the respective lysozyme control groups (A1–A3). Quantitatively, however, on all days of examination, PGC populations in the LA- (B1–B3) and GlcNAc-exposed (C1–C3) embryos are comparatively sparser, while the UMP+UDP-gal-exposed embryos (F1– F3) demonstrated an appreciably denser population of PGCs as compared with those of the lysozyme (A1–A3), UMP (D1–D3), or UDP-gal-exposed (E1–E3) embryos. UR, Urogenital ridge; HG, hindgut. Bar = 20 µm. Inset in each plate presents a part of the corresponding photograph (red-bordered) at higher magnification

Figure 2 depicts the number of PGCs (mean ± SD) per embryo in different study populations during Days 12–14 of embryonic life. There was a significant daywise increase in the number of PGCs in all the groups. Though the numbers of PGCs in the LA- and GlcNAc-exposed rats on each day of examination were comparable, both were significantly lower (P < 0.000001) than those of the respective day-specific controls. As compared with those of the controls, no difference in the total PGC counts was noted in the UMP- or UDP-gal-treated embryos, but in the UMP+UDP-gal-exposed groups, PGC count rose significantly (P ≤ 0.00001) on all days examined.



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  		FIG. 2. Graphical presentation of the comparative numbers of primordial germ cells (mean ± SD) in 12- to 14-day-old embryos exposed in utero to lysozyme (control), LA, GlcNAc, UDP-gal, UMP, and UMP+UDP-gal. Days 12–14: control versus UMP, not significant. Days 12–14: control versus UDP-gal, not significant. Day 12: control versus UMP+UDP-gal, P = 0.00001. Days 13–14: control versus UMP+UDP-gal, P < 0.000001. Days 12–14: GlcNAc versus LA, not significant. Days 12–14: control versus LA/GlcNAc, P < 0.000001


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Primordial germ cells originate at the early developmental stage in an extragonadal location and then migrate to the genital ridges to form the gonad. This locomotion is perhaps controlled in part by the components of the ECM to which the migrating cells bind in a complex and poorly understood way.

Outer cell-surface GalTase on migrating cells has been proposed to interact in a receptor-ligand fashion with glycosyl acceptors that constitute the path of their migration [23]. PGCs are known to possess GalTase [13]; however, it remains as yet uncertain to what extent cell-cell adhesion involving surface GalTase is associated with their locomotion. The objective of the present study was to adjudicate if GalTase played an enzymatic role in the process of PGC migration. To address the issue, we evaluated germ cell migration under perturbed embryonic GalTase activity in utero. The study reported herein was modeled after Runyan et al. [12], who employed the same protocol to study the hypothesized role of GalTase in neural crest cell migration on extracellular glycoconjugate matrices in vitro.

We employed primarily three sets of GalTase activity modifiers—LA, GlcNAc, and UDP-gal—each having its unique mode of action. These test agents were made available to the embryo through microinjections under laparotomy. No precise measure was taken to deliver the modifiers at a very specific and fixed site of the embryos because the Day 10 rat embryos were so tiny (~1.5 mm3) that 3 µl of an aqueous solution of a test material was expected to diffuse into the surroundings and exert effects irrespective of its site of delivery. The possibility of any untoward effect of GalTase deficiency on other major aspects of embryogenesis was discounted because the GalTase-null mouse, created by targeted mutation, is reported to progress through unrestrained embryonic development [24], although the offspring subsequently suffered from delayed spermatogenesis. To exclude any possible nonspecific detrimental effect of the mechanical trauma or physical insult caused by the process of injection on oogonial migration, we performed several control studies. These were designed to examine the effects of mechanical trauma as effected through needle insertion with or without injection of nonspecific pharmacological agents like BSA, GalNAc, UDP-glucose, UMP, and lysozyme. As compared with untreated controls, no alteration in germ cell migration, either in qualitative or quantitative modes, was evident in any of these manipulated groups. For the purpose of comparison, however, we have presented the data on lysozyme- and UMP-injected controls. The basis of using lysozyme as the control protein was that it has structural homology with LA but exerts no influence on GalTase activity. UMP, on the other hand, is a competitive substrate for phosphatase that induces catalytic degradation of UDP-gal. The adjunctive use of an excess of UMP was intended to prevent UDP-gal degradation. UMP-injected controls are also presented to determine the extent to which UMP per se affects germ cell migration.

GalTase and LA are, respectively, the active and catalytically inactive enzymatic subunits of lactose synthase. GalTase transfers galactose from UDP-gal to the terminal GlcNAc acceptor on the oligosaccharide complex of glycoconjugates. With the transferase alone, glucose is not a good acceptor, as it has a high Km [25]. The presence of LA alters the substrate specificity of GalTase from GlcNAc to glucose [26]. Therefore, the theoretical basis of adding LA was to modify the substrate recognition of GalTase and evaluate its consequent effect on germ cell migration. We observed that LA-exposed embryos exhibited deficient numbers of PGCs on the path of migration and had a significant detrimental effect on migration of PGC.

Exogenous GlcNAc was employed as a competitive inhibitor of the putative endogenous GlcNAc that constitutes the ECM and possibly acts as a ligand for GalTase. The idea was that exogenous GlcNAc would compete with endogenous GlcNAc to occupy the GalTase-binding site. Acceptor specificity for transferase is not as stringent as it is for sugar donors. GalTase, which transfers galactose to GlcNAc on some glycoproteins, also transfers galactose to free GlcNAc. The Km of the free GlcNAc, however, appears to be much higher than that for complex glycoconjugates [27]. We therefore employed a relatively high concentration of GlcNAc. As anticipated, a dramatic reduction in the number of PGCs at the expected day-specific sites of the migratory path was observed and the magnitude of response was comparable with that with LA.

Lower numbers of PGCs under perturbed GalTase function argue in favor of a role for GalTase in the process of oogonial migration. Traditionally, GalTase is a biosynthetic component of the Golgi complex, where it catalyzes the transfer of galactose from UDP-gal to terminal GlcNAc residues on growing polysaccharide chains. GalTase that is expressed on the PGC surface possibly represents a short sequence of the cytoplasmic domain that transports a portion of GalTase to the plasma membrane [28]. The surface GalTase functions as a receptor that facilitates the formation of adhesive contacts with the ECM via GlcNAc recognition [29, 30]. Fibronectin and laminin are proposed to act as scaffolds in the ECM on the line of the migratory pathways and support the process of PGC migration [31, 32]. There have been extensive studies that document the formation of cellular processes on laminin matrices both in vitro [10, 33] and in vivo [34]. Reports indicate that, in the mouse, as the PGCs leave the dorsal mesentery, they accumulate on a ribbon of laminin that is formed beneath the epithelial cells lining the coelom [6]. Laminin is known to be a principal GalTase substrate that lines the migratory pathway in the basal lamina [12]. It therefore appears that surface GalTase on the PGC and laminin in the ECM may interact in a receptor-ligand fashion to promote cell-matrix adhesion. It may not be out of context to note that oogonial migration was significantly inhibited under experimental galactose toxicity [19], a condition characterized by a dearth of UDP-gal and attenuated GalTase activity secondary to accumulated gal-1-P [17].

That GalTase functions as a surface receptor in cell-matrix interactions in the process of cellular locomotion has been well documented. However, it remains yet to be uncovered whether GalTase binds its oligosaccharide ligand simply in a lectin-like capacity or it utilizes its enzymatic activity to modify and release its galactosylated product [11]. Whatever be the mode of binding, there should be a mechanism by which GalTase will be released to keep the migratory process going. If GalTase functions noncatalytically, its release should be mediated independent of the presence of UDP-gal. Alternatively, UDP-gal must be made available to the surface-associated enzyme-substrate complex, enabling the catalyzing event to occur and release GalTase. The major shortfall in constructing a hypothesis involving catalytic release of GalTase is that UDP-gal is not normally found in the extracellular environment. Nevertheless, in vitro studies suggest that migrating cells, like fibroblasts, do make a sugar donor available, possibly through a plasma membrane transporter, to galactosylate their substrata in the underlying matrix coincident with migration upon them [11, 35]. Consistent with this is the finding that translocation of neural crest cells in vitro showed a dose-dependent increase in the mean migration rate following addition of UDP-gal [12]. To assess if the same mechanism is operative in the migration of PGC, we tested whether exogenous UDP-gal affected oogonial migration. The theoretical strategy was to induce premature catalysis of the putative GalTase reaction and thereby release GalTase from its extracellular matrix substrate, and assess if it stimulates the process of oogonial migration. Contrary to our expectation, however, our initial approach proved unsuccessful. Exposure to UDP-gal alone was not found to exert any promotional influence on the rate of oogonial migration. This was possibly attributable to high susceptibility of UDP-gal to catalytic degradation by phosphatases. To circumvent this problem, a 10-fold excess level of UMP was administered as an adjunct with UDP-gal. The unaltered PGC population in the UMP-treated embryos proved that UMP did not influence PGC migration on its own right, but when administered simultaneously with UDP-gal, it significantly increased the PGC population at all the day-specific sites. Being a substrate for phosphatase, UMP could prevent degradation of UDP-gal and increase its effective concentration. This observation bears the testimony that PGC migration perhaps involves the catalytic function of GalTase that utilizes UDP-gal as a substrate.

The present experimental approach, however, has limitations. Considering the known biochemical effects of the modifiers, it appears probable that the drastic reduction of germ cell number is attributed to attenuated embryonic GalTase activity. But it remains yet to be ascertained that the effect was the consequence of perturbed locomotion rather than adversely affected oogonial proliferation and/or survival that may also account for the decreased PGC number. Accordingly, substantiation of the proposed role of GalTase needs further study that will discount the possibilities of the effects of inhibited GalTase on germ cell survival or proliferation. We therefore conclude that the observation provided herein may be merely viewed as a prelude to what the future holds.


   ACKNOWLEDGMENTS
 
We wish to thank H.N. Ray, Indian Institute of Chemical Biology, and Syed R. Kabir for their assistance in photography.


   FOOTNOTES
 
1 Supported by grants from the Department of Science and Technology (SP/ SO/B31/97) and the Council of Scientific and Industrial Research, New Delhi, India. This work was presented in part at the 19th Annual Meeting of the European Society of Human Reproduction and Embryology, Spain, 2003. Back

2 Correspondence. FAX: 91 33 2473 5197; snkabir{at}iicb.res.in Back

Received: 17 February 2004.

First decision: 4 March 2004.

Accepted: 22 July 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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